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1

Qiu, Hong. "Leukotrienes and leukotriene receptors : potential roles in cardiovascular diseases /." Stockholm, 2007. http://diss.kib.ki.se/2007/978-91-7357-056-5/.

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2

Fehler, Martina. "Investigation of trace amine receptors in the cardiovascular systems." Thesis, Cardiff University, 2008. http://orca.cf.ac.uk/55739/.

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Trace amines (TAs), including p-phenylethylamine (p-PEA), tyramine and octopamine are structurally and functionally related to biogenic amines such as catecholamines and serotonin and to amphetamines. They are present in trace levels in the nervous system and in chocolate, cheese and wine. TAs are usually regarded as indirectly-acting sympathomimetic amines (ISAs) exerting vasoconstriction via a-adrenoceptors. However, they also stimulate trace amine-associated receptors (TAARs), of which only TAAR1 and TAAR4 are sensitive to TAs. The aim of the thesis was to examine whether vasoconstriction by TAs in blood vessels is via ISA or TA mechanisms. TAs caused concentration-related and endothelium-independent contractions in rat isolated aortic rings in the presence of prazosin (ai-adrenoceptor antagonist), cocaine (catecholamine uptake inhibitor), ICI-118,551-adrenoceptor antagonist) and pargyline (MAO A and B inhibitor). The persistent and inhibitor-independent contractions suggest that mechanisms other than ISA and a- and p- adrenoceptor stimulation are involved, possibly TAARs. Differences in the profile of vasoconstrictor activities to a range of TAs were identified in rat and guinea-pig aorta, suggesting species variations in receptor distribution. Tyramine was identified as a partial agonist in isolated rat aorta and an antagonist of other TAs in this tissue. Finally, the presence of TAAR1 mRNA and protein was demonstrated for the first time in rat aorta by RT-PCR and Western blotting, respectively. Most information about TAs relates to studies which have been done on the brain, or cloned receptors expressed in transfected cells. This study of different TAs and structurally related derivatives in aortic tissues has expanded the knowledge of the vasoconstrictor effects of TAs in isolated tissues. The molecular biological confirmation of the presence of TAAR1 and the pharmacological findings regarding the effects of TAs in rat aortic rings might explain their hypertensive effects and their role in coronary heart disease and migraine headache.
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3

Urayama, Kyoji. "Role of prokinenticins and their receptors in cardiovascular system." Université Louis Pasteur (Strasbourg) (1971-2008), 2008. https://publication-theses.unistra.fr/restreint/theses_doctorat/2008/URAYAMA_Kyoji_2008.pdf.

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Les maladies cardiovasculaires restent la première cause de mortalité et deviennent vite la préoccupation de santé numéro un dans le monde. L'identification de nouveaux facteurs responsables de la régulation du système cardiovasculaire et la génération des modèles animaux des maladies cardiovasculaires sont des étapes importantes pour mieux comprendre les pathologies de l'insuffisance cardiaque incluant les maladies cardiaques congénitales et pour développer des nouvelles thérapies. Les prokinéticines sont des facteurs angiogènic potentiels qui se liant aux récepteurs couplés aux protéines G (PKR1 et PKR2) pour initier leurs effets biologiques. D'abord, nous émettons l’hypothèse que la voie de signalisation du récepteur 1 de la prokinéticine (PKR1) peut contribuer à la survie des cardiomyocytes ou à la protection du coeur après un infarctus du myocarde. Puisque nous avons montré que la prokinéticine-2 et PKR1 sont exprimés dans le coeur des souris adultes et dans les cellules cardiaques, nous avons étudié le rôle de la prokinéticine-2 et PKR1 sur la fonction des cardiomyocytes. Dans les cardiomyocytes et les cellules H9c2, la prokinéticine-2 ou la surexpression de PKR1 active Akt pour protéger les cardiomyocytes contre le stress oxydatif. Puis nous avons déterminé si le transfert de gène, ADN codant PKR1, intracardiaque peut améliorer les fonctions du myocarde après l'infarctus du myocarde dans le modèle de souris. Le transfert transitoire du gène PKR1 après ligation de l’artère coronaire réduit la mortalité et préserve la fonction du ventricule gauche en favorisant la néovascularisation et en réduisant l’apoptose des cardiomyocytes. Nos résultats suggèrent que PKR1 peut représenter une cible thérapeutique originale pour limiter les lésions du myocarde suite à une ischémie. Ensuite, nous avons déterminé les conséquences pathologiques suite à la surexpression de PKR1 dans les cardiomyocytes in vivo. Nous avons généré des souris transgéniques surexprimant PKR1 dans les cardiomyocytes (TG-PKR1) en utilisant le promoteur α-MHC. Les coeurs TG-PKR1 ne montrent aucune anomalie spontanée dans les cardiomyocytes, mais on observe une augmentation de la densité capillaire et des artérioles. De plus, en surexprimant PKR1 dans les cardiomyoblasts H9c2 ou dans les coeurs transgéniques l'expression de la prokinéticine-2 est augmentée. La surexpression de PKR1 dans les cardiomyocytes augmente la libération son propre ligand la prokinéticine-2 qui agit comme un facteur paracrine, en déclenchant la prolifération/différentiation des cellules progénitrices de l’épicarde (EPDCs) pour induire la néovascularisation. Cette étude offre un nouvel aperçu des stratégies thérapeutiques possibles ayant pour but la restauration de la pluripotence des cellules adultes EPDCs pour promouvoir la neovascularisation en induisant la voie de signalisation de PKR1 dans les cardiomyocytes. Comme PKR1 et PKR2 sont identiques à 85 % et sont exprimés dans les tissus cardiovasculaires, nous avons ensuite déterminé les conséquences pathologiques de la surexpression du récepteur 2 de la prokinéticine (PKR2) dans les cardiomyocytes in vivo. Nous avons généré des souris transgéniques surexprimant PKR2 dans les cardiomyocytes (TG-PKR2) en utilisant le promoteur α-MHC. Nous émettons une hypothèse que PKR2 peut aussi contribuer à la croissance des cardiomyocytes et à la vascularisation. Les coeurs TG-PKR2 ont montré une augmentation de l'expression des gènes de l’hypertrophie et de l'hypertrophie excentrique montrant l'augmentation des diamètres du ventricule gauche et l’augmentation de la longueur des cardiomyocytes. L'analyse morphologique quantitative a montré que les coeurs TG-PKR2 ont une densité des microvaisseaux et un nombre de points de branchement normaux, cependant les coeurs TG-PKR2 ont montré une augmentation des formes et des ultrastructures anormales des cellules endothéliales ce qui indiquent la fenestration des vaisseaux sanguins. L'application de milieu conditionné par les cardioblasts H9c2 surexprimant PKR2 de façon significative induit une diminution de la localisation de jonction serrée ZO-1 dans les cellules endothéliales cardiaques, mimant le modèle TG-PKR2. Ces conclusions fournissent la première évidence génétique que la voie de la signalisation de PKR2 dans les cardiomyocytes cause l'hypertrophie excentrique par régulation autocrine et a diminué l'intégrité des cellules endothéliales par régulation paracrine sans induire l’angiogenèse. Ces souris TG-PKR2 peuvent fournir un nouveau modèle génétique des maladies du coeur. Ensuite nous avons déterminé si PKR2 peut directement induire la fenestration dans les cellules endothéliales cardiaques. Les cellules endothéliales cardiaques surexprimant PKR2 ont montré une augmentation de l'expression de caveolin-1 et une diminution de l'expression de la protéine de jonction serrée ZO-1. De plus, ces cellules ont montré une perturbation de la localisation ZO-1. Ces données indiquent que PKR2 peut induire le dysfonctionnement de la barrière des cellules ayant pour effet directe la fenestration dans les cellules endothéliales cardiaques. Après la stimulation des cellules endothéliales surexprimant PKR2 par la prokinéticine-2, nous avons observé l'internalisation et réduction de la protéin VE-cadhérine. Ces données indiquent la possibilité que la protéine Gα12 couplée avec PKR2 induit un dysfonctionnement de la barrière des cellules endothéliales cardiaques. Pour conclure, pour la première fois nous avons montré que la balance entre l'activation de la voie de signalisation de PKR1 et de PKR2 pouvait être très importante pour protéger les cardiomyocytes des lésions causées par l'ischémie et/ou d’induire la neovascularisation dans le coeur, puisque les rôles des récepteurs de la prokinéticine dans le coeur sont impliqués dans la survie des cellules et l’angiogenèse via PKR1 et dans l'hypertrophie cardiaque et la fenestration via PKR2
Cardiovascular disease remains the number one cause of mortality and is fast becoming the number one health concern worldwide. Identification of new factors responsible for regulation of the cardiovascular system and generation of animal models of cardiovascular disease are important steps to better understand the pathogenesis of the heart failure including congenital heart disease and to develop new therapies. Prokineticins are potent angiogenic factors that bind to two G protein-coupled receptors (PKR1 and PKR2) to initiate their biological effects. First, we hypothesize that prokineticin receptor-1 (PKR1) signaling may contribute to cardiomyocyte survival or repair in myocardial infarction. Since we showed that prokineticin-2 and PKR1 are expressed in adult mouse heart and cardiac cells, we investigated the role of prokineticin-2 and PKR1 on cardiomyocytes function. In cardiomyocytes and H9c2 cells, prokineticin-2 or overexpressing PKR1 activates Akt to protect cardiomyocytes against oxidative stress. We thus, further investigated whether intramyocardial gene transfer of DNA encoding PKR1 may rescue the myocardium against myocardial infarction in mouse model. Transient PKR1 gene transfer after coronary ligation reduces mortality and preserves left ventricular function by promoting neovascularization and protecting cardiomyocytes. Our results suggest that PKR1 may represent a novel therapeutic target to limit myocardial injury following ischemic events. Next, we investigated the pathological consequences of overexpressing PKR1 in cardiomyocytes in vivo. We have generated transgenic mice overexpressing PKR1 in cardiomyocytes (TG-PKR1) using α-MHC promoter. TG-PKR1 hearts displayed no spontaneous abnormalities in cardiomyocytes but showed an increased number of capillary density and arterioles. Moreover, overexpressing PKR1 in H9c2 cardiomyoblasts or in TG-PKR1 hearts upregulated prokineticin-2 expression. Cardiomyocyte-PKR1 signaling upregulates its own ligand prokineticin-2 that acts as a paracrine factor, triggering Epicardial-derived Progenitor cells (EPDCs) proliferation/differentiation to induce neovascularization. This study provides a novel insight for possible therapeutic strategies aiming at restoring pluripotency of adult EPDCs to promote neovasculogenesis by induction of cardiomyocyte PKR1 signaling. Since PKR1 and PKR2 are 85% identical and expressed in cardiovascular tissues, next we investigated the pathological consequences of overexpressing prokineticin receptor-2 (PKR2) in cardiomyocytes in vivo. We have generated transgenic mice overexpressing PKR2 in cardiomyocytes (TG-PKR2) using α-MHC promoter. We hypothesize that PKR2 may also contribute to cardiomyocyte growth and vascularization. TG-PKR2 hearts showed increased hypertrophic gene expression and eccentric hypertrophy which showed that increased left ventricular diameters and increased the length of cardiomyocytes. Quantitative morphological analysis showed that TG-PKR2 hearts have a normal micro vessel density and number of branch points, however TG-PKR2 hearts showed increased abnormal endothelial shape and ultrastucture which indicate the fenestration of blood vessels. Application of media conditioned by H9c2 cardioblast cells overexpressing PKR2 significantly induced impaired ZO-1 tight junction localization in cardiac endothelial cells, mimicking the TG-PKR2 model. These findings provide the first genetic evidence that cardiomyocyte-PKR2 signaling leads to eccentric hypertrophy in an autocrine regulation, and impaired endothelial integrity in a paracrine regulation without inducing angiogenesis. These TG-PKR2 mice may provide a new genetic model for heart disease. Next we investigated whether PKR2 can directly induce fenestration into cardiac endothelial cells. PKR2 overexpressing cardiac endothelial cells showed increased caveolin-1 expression and decreased ZO-1 tight junction protein expression. Moreover, those cells showed disruption of ZO-1 localization. These data indicate PKR2 can induce cell barrier dysfunction resulting in fenestration into cardiac endothelial cells as a direct effect. After prokineticin-2 stimulation in PKR2 overexpressing cardiac endothelial cells, we observed internalization and downregulation of VE-cadherin. These data indicate the possibility of Gα12 coupling with PKR2 to induce cell barrier dysfunction in cardiac endothelial cells. As a conclusion, for the first time we have shown that the balance between the activation of PKR1 and PKR2 signaling could be very important to prevent cardiomyocytes from ischemic insult and/or to induce neovascularization in heart, since the roles of prokineticin receptors in heart are involved in cell survival and angiogenesis via PKR1 and in cardiac hypertrophy and fenestration via PKR2
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McLeod, Janet Leigh, and janet mcleod@deakin edu au. "The natriuretic peptides and their receptors in the brain of the amphibian, Bufo marinus." Deakin University. School of Biological and Chemical Sciences, 1999. http://tux.lib.deakin.edu.au./adt-VDU/public/adt-VDU20071024.112730.

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The natriuretic peptides, atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP) and C-type natriuretic peptide (CNP) are members of a family of hormones that play an important role in mammalian fluid and electrolyte balance. In the periphery, natriuretic peptides reduce blood volume and subsequently blood pressure by increasing renal natriuresis and diuresis and relaxation of vascular smooth muscle. The actions of natriuretic peptides are mediated via two membrane-linked guanylate cyclase receptors (NPR-GC); natriuretic peptide receptor-A (NPR-A) which has a high affinity for ANP and BNP; and natriuretic peptide receptor-B (NPR-B)which has the greatest affinity for CNP. A third receptor not linked to guanylate cyclase, natriuretic peptide receptor-C (NPR-C) also exists, which binds to ANP, BNP and CNP with a relatively equal affinity, and is involved with clearance of the peptides from the circulation and tissues. The natriuretic peptides are present in the brain and are particularly predominant in cardiovascular and fluid and electrolyte regulating areas such as the anteroventral third ventricle (AV3V) region. This distribution has led to the suggestion natriuretic peptides play a neuromodulatory role in the central control of fluid homeostasis. Natriuretic peptides in the brain have been observed to inhibit the release of other fluid and electrolyte regulating hormones such as arginine vasopressin (AVP) and angiotensin II (AII). Natriuretic peptides have also been identified in the non-mammalian vertebrates although information regarding the distribution of the peptides and their receptors in the non-mammalian brain is limited. In amphibians, immunohistochemical studies have shown that natriuretic peptides are highly concentrated in the preoptic region of the brain, an area believed to be analogous to the A\T3\ region in mammals, which suggests that natriuretic peptides may also be involved in central fluid and electrolyte regulation in amphibians. To date, CNP is the only natriuretic peptide that has been isolated and cloned from the lower vertebrate brain, although studies on the distribution of CNP binding sites in the brain have only been performed in one fish species. Studies on the distribution of ANP binding sites in the lower vertebrate brain are similarly limited and have only been performed in one fish and two amphibian species. Moreover, the nature and distribution of the natriuretic peptide receptors has not been characterised. The current study therefore, used several approaches to investigate the distribution of natriuretic peptides and their receptors in the brain of the amphibian Bufo marinus. The topographical relationship of natriuretic peptides and the fluid and electrolyte regulating hormone arginine vasotocin was also investigated, in order to gain a greater understanding of the role of the natriuretic peptide system in the lower vertebrate brain. Immunohistochemical studies showed natriuretic peptides were distributed throughout the brain and were highly concentrated in the preoptic region and interpeduncular nucleus. No natriuretic peptide-like immunoreactivity (NP-IR) was observed in the pituitary gland. Arginine vasotocin-like immunoreactivity (AvT-IR) was confined to distinct regions, particularly in the preoptic/hypothalamic region and pituitary gland. Double labelling studies of NP-JR and AvT-IR showed the peptides are not colocalised in the same neural pathways. The distribution of natriuretic peptide binding sites using the ligands 125I-rat ANP (125I-rANP) and 125I-porcine CNP (125I-pCNP) showed different distributions in the brain of B. marinus. The specificity of binding was determined by displacement with unlabelled rat ANP, porcine CNP and C-ANF, an NPR-C specific ligand. 125I-rANP binding sites were broadly distributed throughout the brain with the highest concentration in pituitary gland, habenular, medial pallium and olfactory region. Minimal 125I-rANP binding was observed in the preoptic region. Residual 125I-rANP binding in the presence of C-ANF was observed in the olfactory region, habenular and pituitary gland indicating the presence of both NPR-GC and NPR-C in these regions. 125I-pCNP binding was limited to the olfactory region, pallium and posterior pituitary gland. All 125I-pCNP binding was displaced by C-ANF which suggests that CNP in the brain of B. marinus binds only to NPR-C. Affinity cross-linking and SDS-PAGB demonstrated two binding sites at 136 kDa and 65 kDa under reducing conditions. Guanylate cyclase assays showed 0.1 µM ANP increased cGMP levels 50% above basal whilst a 10-fold higher concentration of CNP was required to produce the same result. Molecular cloning studies revealed a 669 base pair fragment showing 91% homology with human and rat NPR-A and 89% homology with human, rat and eel NPR-B. A 432 base pair fragment showing 67% homology to the mammalian NPR-C and 58% homology with eel NPR-D was also obtained. The results show natriuretic peptides and their receptors are distributed throughout the brain of B. marinus which indicates that natriuretic peptides may participate in a range of regulatory functions throughout the brain. The potential for natriuretic peptides to regulate the release of the fluid and electrolyte regulating hormone AVT also exists due to the high number of natriuretic peptide binding sites in the posterior pituitary gland. At least two populations of natriuretic peptide receptors are present in the brain of B. marinus, one linked to guanylate cyclase and one resembling the mammalian clearance receptor. Furthermore, autoradiography and guanylate cyclase studies suggest ANP may be the major ligand in the brain of B. marinus, even though CNP is the only natriuretic peptide that has been isolated from the lower vertebrate brain to date.
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Williams, Maro R. I. 1974. "Dehydroepiandrosterone action in the cardiovascular system." Monash University, Dept. of Medicine, 2002. http://arrow.monash.edu.au/hdl/1959.1/7927.

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6

Farmer, Louise Katie. "The molecular basis of antagonism at cardiovascular P2X1 and P2X4 receptors." Thesis, University of Leicester, 2014. http://hdl.handle.net/2381/40322.

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Structural information for the zebrafish P2X4 receptor in both an agonist bound and unbound resting state provided a major advance in understanding agonist action and has given insight into movement that occurs in the receptor upon ATP binding. Despite agonist action now being well characterised, the molecular basis of antagonism is poorly understood. In this thesis the mechanism of antagonist action at the hP2X1 receptor has been investigated through determining properties of chimeras and mutant receptors based on differences between antagonist sensitive and insensitive P2X receptors. The antagonists suramin, NF449 and PPADS potently inhibit the human P2X1 receptor but have little or no action at the rat P2X4 receptor. The extracellular loop of the hP2X1 receptor was shown to determine antagonist sensitivity and was therefore split into four sections, residues of which were swapped with corresponding residues of the antagonist insensitive rP2X4 receptor and vice versa. Sub-chimeras and point mutations were then made to identify particular residues and regions which contribute to antagonist action. These experiments identified two regions important for NF449 binding at the receptor. These are a cluster of four positively charged residues at the base of the cysteine rich head region (136-140) and three residues located just below them (T216, H224 and Q231). An NF449 bound model of the hP2X1 receptor has been generated. The introduction of the four positively charged residues at the base of the cysteine rich head region to the rP2X4 receptor introduced suramin and PPADS sensitivity to this previously insensitive receptor. This mutation is thought to cause a conformational change which allows the antagonist to bind at residues which are already present in the wildtype receptor. In summary this thesis has advanced the understanding of antagonist action at the hP2X1 receptor and the antagonist insensitivity of the rP2X4 receptor.
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Ratcliffe, Charlotte Fenton. "Cloning and functional co-expression of cardiovascular receptors and ion channels." Thesis, University of Leicester, 1996. http://hdl.handle.net/2381/35135.

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There is an expanding family of cyclic nucleotide-gated cation channels (CNGCs) with expression of family members reported in rod and cone photoreceptor cells, olfactory epithelium, heart, kidney, sperm and aorta. Although functions have been assigned to CNGCs in sensory cells, the function of such channels in non-sensory cells is unknown. A PCR-based screen showed that a CNGC is expressed throughout bovine heart tissue and also in bovine aorta, a bovine aorta endothelial cell line and a human umbilical vein endothelial cell line. Sequence data from these amplified products showed that the CNGC expressed in bovine heart and vasculature is highly related to the bovine rod photoreceptor channel. This was also the case for PCR-generated clones spanning the entire coding sequence of the CNGC from porcine coronary artery smooth muscle tissue. Cyclic GMP is an important messenger in vascular smooth muscle relaxation and therefore this CNGC may play a key role in this process. The second messenger pathways which may be involved in the gating of cardiovascular CNGCs have also been studied by attempting to heterologously co-express a cGMP-generating receptor, ANP-RA, with a CNGC in HEK293 cells. The inward rectifier K+ channel subunits Kir 3.1 and Kir 3.4 have been heterologously co-expressed in MEL cells using a mammalian expression vector which incorporates the ?-globin LCR and promoter allowing high levels of gene expression in a 'position independent' manner. Electrophysiological analysis of these co-expressing cell lines shows that Kir 3.1 and Kir 3.4 form a heteromultimeric ion channel complex which displays the features of the native G-protein activated atrial muscarinic K+ channel, KACh, and it is probable that these two inward rectifier channel subunits are major components of KACh.
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Moore, C. "The role of neuronal nicotinic acetylcholine receptors in central cardiovascular regulation." Thesis, University College London (University of London), 2007. http://discovery.ucl.ac.uk/1444883/.

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The central effect of nicotine on cardiovascular regulation has been extensively studied. However, due to its unselective nature for nicotinic acetylcholine receptors (nAChR) the involvement of specific nAChRs at sites in the brain, in central nervous cardiovascular regulation remains unclear. The effects of intracerebroventricular (i.c.v.) and intracisternal (i.e.) injections of the a7 selective agonist, PSAB-OFP, and the a4p2 selective agonist, TC-2559, were investigated on blood pressure (BP), heart rate (HR) and renal sympathetic nerve activity (RSNA) compared with nicotine, in the anaesthetised rats. PSAB-OFP and TC-2559 i.c.v. caused a delayed dose-related increase in BP and RSNA. When given i.e. the action was similar except the rise in BP was more immediate. The possibility that the pressor response was partly due to the agonists causing the release of the vasoconstrictor vasopressin into the circulation was tested by repeating the i.c.v. and i.e. injections of the agonists in the presence of a selective vasopressin Via antagonist. In the presence of Vi antagonist (i.v.), PSAB-OFP and TC-2559 (i.c.v.) now induced no change in BP or RSNA however i.e., the increase in BP and RSNA was delayed with TC-2559, while PSAB-OFP caused a decrease in BP and no change in RSNA. The cardiovascular effects of i.c.v. PSAB-OFP and TC-2559 in the presence of Vi receptor antagonist (i.c.v.) were also completely blocked. PSAB-OFP and TC-2559 (i.e.) in rats pre-treated with Vi antagonist (i.e.), no longer produced an increase in BP and RSNA. However, the delayed fall in BP caused by PSAB-OFP was potentiated. Nicotine i.c.v. caused a dose-related increase in BP and renal sympathoinhibition while i.e. the rise in BP was larger and now associated with a bradycardia. In the presence of Vj antagonist (i.v.), nicotine's (i.c.v.) cardiovascular effects were blocked however nicotine i.e. caused a decrease in BP, RSNA and HR. In the presence of Vi antagonist (i.c.v.), nicotine caused no change in RSNA, but BP still increased. In the presence of Vi antagonist (i.e.), nicotine i.e. induced a decrease in RSNA and HR, with no change in BP. This study indicates that activation of a4p2 and
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Katugampola, Sidath Dhammika. "Vasoactive and de-orphanised G protein coupled receptors in human cardiovascular disease." Thesis, University of Cambridge, 2002. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.620196.

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10

Sellers, Kathleen Walworth. "Role of brain soluble epoxide hydrolase in cardiovascular function." [Gainesville, Fla.] : University of Florida, 2004. http://purl.fcla.edu/fcla/etd/UFE0008356.

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Thesis (Ph.D.)--University of Florida, 2004.
Typescript. Title from title page of source document. Document formatted into pages; contains 156 pages. Includes Vita. Includes bibliographical references.
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11

Foley, Charles Michael. "The cardiovascular effects of activation of metabotropic glutamate receptors in the nucleus tractus solitarius /." free to MU campus, to others for purchase, 1999. http://wwwlib.umi.com/cr/mo/fullcit?p9946255.

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Foley, C. Michael. "The cardiovascular effects of activation of metabotropic glutamate receptors in the nucleus tractus solitarius." free to MU campus, to others for purchase, 1999. http://wwwlib.umi.com/cr/mo/fullcit?p9946255.

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13

Giannattasio, Bartolomeo. "Characterization of ATP receptors and voltage-dependent calcium ion channels in cardiovascular cells." Case Western Reserve University School of Graduate Studies / OhioLINK, 1993. http://rave.ohiolink.edu/etdc/view?acc_num=case1060781044.

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14

Ho, Ming-Fen. "An Investigation of Gene Variants in Adenosine Receptors and Changes with Essential Hypertension." Thesis, Griffith University, 2012. http://hdl.handle.net/10072/365325.

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Alternative splicing is increasingly emerging as a key mechanism that contributes to the transcript and protein complexity observed in human and other species. Alternative splicing frequently occurs in human genes, approximately 70% and generates different protein isoforms in specific tissue types and pathological conditions. A splice variant can form a new isoform of the protein to modify the function. However, it is also possible that the transcripts lack coding capacity and fail to be involved in regulatory activities. Essential hypertension is the most common cardiovascular disease, the prevalence of which is approximately 26% worldwide. Additionally, essential hypertension is considered to be a multifactoral disorder and its aetiology has yet to be clearly identified. It is known whether adenosine receptor subtypes mediating vasodilator responses in vascular tissue vary according to the blood vessel location. However, it is unknown that adenosine receptor splice variants are expressed in cardiovascular tissues and whether the gene expression patterns have a role in the development of hypertension.
Thesis (PhD Doctorate)
Doctor of Philosophy (PhD)
School of Medicine
Griffith Health
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15

Knowles, Ian David. "The role of 5-HT←2 receptors in central cardiovascular regulation in anaesthetized rats." Thesis, University College London (University of London), 1999. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.313783.

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Frithiof, Robert. "Cerebral mechanisms in cardiovascular control : studies on haemorrhage and effects of sodium /." Stockholm : Karolinska institutet, 2007. http://diss.kib.ki.se/2007/978-91-7357-255-2/.

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17

Atala, Magda Maya. "Influência dos polimorfismos do gene do receptor adrenérgico beta2 na regulação cardiovascular de jovens normotensos." Universidade de São Paulo, 2006. http://www.teses.usp.br/teses/disponiveis/5/5131/tde-17102014-114153/.

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O sistema nervoso (SN) autonômico é fundamental na regulação cardiovascular. A análise da variabilidade da freqüência cardíaca (VFC), no domínio do tempo e da freqüência, expressa a modulação autonômica cardíaca, pois reflete a atividade do SN simpático (receptores adrenérgicos) e do SN parassimpático (receptores muscarínicos) sobre Nó Sinoatrial. As variantes genéticas funcionais (polimorfismos) do receptor adrenérgico beta2 vêm sendo associadas a diferentes estados funcionais do receptor e a diversos fenótipos cardiovasculares. Investigamos em 218 de jovens normotensos (entre 18 a 30 anos) a associação dos polimorfismos do receptor adrenérgico beta2 tipo Gln27Glu (Gln/Gln, Gln/Glu e Glu/Glu) e tipo Arg16Gly (Arg/Arg, Arg/Gly e Gly/Gly) com o perfil antropométrico e com os fenótipos cardiovasculares: o balanço autonômico para o coração (análise da VFC), a noradrenalina sérica, e variáveis hemodinâmicas, que foram registradas durante o repouso (5min) e o tilt test (teste de estresse postural, 5 min). Resultados: polimorfismo beta2 tipo Gln27Glu - comparados aos portadores do genótipo Gln/Gln, os indivíduos com genótipos Glu/Glu e Gln/Glu apresentaram uma menor relação cintura/quadril (p=0,008) e uma maior atividade simpática em resposta ao tilt teste, ou seja, maior aumento do componente LF (p=0,027) e maior relação LF/HF (p=0,014); polimorfismos beta2 tipo Arg16Gly - portadores do genótipo Arg/Arg apresentaram maior queda do índice alfa durante o tilt test, comparados aos outros genótipos; associação de polimorfismos (haplótipos) - portadores do haplótipo Gln27Gln/Arg16Gly apresentaram maior incremento da FC quando comparados aos portadores dos haplótipos Gln27Gln/Gly16Gly (p=0,06). Conclusão: foi possível detectar que os polimorfismos do receptor adrenérgico beta2 tipo Gln27Glu e tipo Arg16Gly têm impacto sobre o balanço autonômico cardíaco, respectivamente, aumentando a atividade simpática para o coração e diminuindo a atividade baroreflexa durante manobra de estresse postural, em indivíduos jovens normotensos
The autonomic nervous system (NS) has a pivotal role in cardiovascular control. Time domain and spectral analyzes of heart rate variability (HRV) indicates cardiac autonomic modulation, since it reflects the sympathetic (adrenergic receptors) and parasympathetic (muscarinic receptors) nerve activity over the Sinoatrial Node. Polymorphisms of the adrenergic receptor beta2 have been associated to different functional state of receptor and cardiovascular phenotypes. We analyzed in 218 young normotensive subjects (18-30 years old) the association of polymorphisms of the adrenergic receptor type Gln27Glu (Gln/Gln, Gln/Glu e Glu/Glu) and type Arg16Gly (Arg/Arg, Arg/Gly e Gly/Gly) with anthropometric data and cardiovascular phenotypes: cardiac autonomic balance (HRV), norephinefrine levels, and hemodynamic parameters, which were registered during rest (5min) and tilt test (5 min). Results: beta2 polymorphism type Gln27Glu - compared to subjects with genotype Gln/Gln, subjects with genotype Glu/Glu e Gln/Glu showed a lower WHR (p=0,008) and a higher increase in sympathetic activity during tilt teste, i.e., a higher increase in LF component (p=0,027) and LF/HF relation (p=0,014); beta2 polymorphism type Arg16Gly - subjects with genotype Arg/Arg demonstrated a higher decrease in alpha index during tilt test, compared to other genotypes; polymorphism association (haplotype) - subjects with Gln27Gln/Arg16Gly had a higher increase in hear rate compared to subjects with haplotype Gln27Gln/Gly16Gly (p=0,06). Conclusion: it was possible to detect in young normotensive subjects that polymorphisms of the adrenergic receptor type Gln27Glu and type Arg16Gly have an impact over cardiac autonomic balance, respectively, increasing the cardiac sympathetic activity and decreasing the baroreflex sensibility during tilt test
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18

Nelson, Michael Bruce. "The Role of Receptors for Advanced Glycation End-Products (RAGE) and Ceramide in Cardiovascular Disease." BYU ScholarsArchive, 2015. https://scholarsarchive.byu.edu/etd/4423.

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Type 2 diabetes and cigarette smoke exposure are associated with an increased risk of cardiovascular complications. The role of advanced glycation end-products (AGEs) is already well-established in numerous comorbidities including cardiomyopathy. Given the role of AGEs and their receptor, RAGE, in activating inflammatory pathways, we sought to determine whether ceramides could be a mediator of RAGE-induced altered heart mitochondrial function. Using an in vitro model, we treated H9C2 cardiomyocytes with carboxy-methyl lysine-BSA, followed by mitochondrial respiration assessment. We found that mitochondrial respiration was significantly impaired in AGE-treated cells, but not when co-treated with myriocin, an inhibitor of de novo ceramide biosynthesis. Moreover, we exposed WT and RAGE KO mice to side-stream cigarette smoke and found reduced mitochondrial respiration in the left ventricle myocardium from WT mice, but the RAGE KO mice were protected from this effect. Finally, conditional over-expression of RAGE in the lungs of mice also elicited a robust increase in left ventricular ceramides. Altogether, these findings suggest a RAGE-ceramide axis as an important contributor to cardiomyopathy.
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19

Cheung, Ngai. "Expression of vascular endothelial growth factor and its receptors in tumours /." Hong Kong : University of Hong Kong, 1998. http://sunzi.lib.hku.hk/hkuto/record.jsp?B20720981.

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20

Cruz, María Natalia. "Gender-related small artery function : implications for estrogenic compounds /." Stockholm, 2006. http://diss.kib.ki.se/2006/91-7357-000-1/.

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21

Foryst-Ludwig, Anna [Verfasser]. "Obesity-related cardiovascular and metabolic diseases : the role of estrogens, estrogen receptors and PPARgamma / Anna Foryst-Ludwig." Berlin : Medizinische Fakultät Charité - Universitätsmedizin Berlin, 2014. http://d-nb.info/1052530788/34.

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22

張毅 and Ngai Cheung. "Expression of vascular endothelial growth factor and its receptors in tumours." Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 1998. http://hub.hku.hk/bib/B31220587.

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23

Afshari, Reza. "The cardiovascular effects of opioid analgesics : studies on the role of opioid and non-opioid receptors in man." Thesis, University of Edinburgh, 2006. http://hdl.handle.net/1842/28232.

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In this thesis, a series of related studies on opioids are reported. In epidemiological studies of opioid overdose it is shown that opioid overdose has increased 14 times more than other overdoses in Edinburgh in the past 4 decades. I also discussed the predisposing factors for overdose. I developed and calculated a series of toxicity indices for opioids in Scotland, and used hospital discharge data, poisons information statistics (telephone enquiries/TOXBASE accesses) and prescription data to calculate fatality indices (FTI) and minimise the effects of confounders on the traditional FTI which uses only prescription volume as the denominator. I used an identical methodology to relate non-fatal consequences of overdose to prescriptions and proposed toxic morbidity indices (TMIs). I suggest an integrated approach by using both FTIs and TMIs as new methods for toxico-vigilance. Using this methodology I demonstrated that co-proxamol has a10 times excess risk of fatality in comparison to co-codamol and co-dydramol, while TMIs are similar. This demonstrates the inherent toxicity of the drug in overdose, and led, in part, to withdrawal of this drug in the UK. Further I showed in patients that QRS duration is prolonged in co-proxamol overdose, an effect which was dose dependent, suggesting sodium channel blockade as a potential cause of its excess mortality in overdose. I showed from mortality statistics that dihydrocodeine appears safer than methadone. I also estimated diamorphine illicit availability from overdose rates in Edinburgh. I introduced a comparison of mortality from single agent in comparison to multiple agent overdose (MSDPR) as a measure of risk from cointoxications. I showed that diamorphine, morphine and codeine are significantly more dangerous in co-intoxication than other opioids. Studies on the cardiovascular effects of opioids in overdose and in volunteers were then performed. It has been suggested previously that therapeutic doses morphine have no effects on the cardiovascular system in man in the supine position. I first showed acute depressor effects of dihydrocodeine and methadone overdose on peripheral systolic, diastolic, pulse, and aortic and end systolic pressures, and 02 saturation in dihydrocodeine overdose in comparison to a parallel control group. I was able to exclude any effect on arterial stiffness. I showed that 02 saturation under 95% is a marker of haemodynamic depressant effects of dihydrocodeine. Later in a controlled trial in healthy volunteers, I verified the cardiovascular depressor effects of intravenous morphine in doses to a maximum of 16 mg. These effects were not dose dependent. There was also no relationship to change in reaction time, and no major change in plasma concentrations of histamine or catecholamines. Lower 02 saturation, and higher end tidal volume C02 potentially contributed to the haemodynamic effects. I showed that intra venous morphine decreased aortic and peripheral systolic, diastolic, mean, pulse, end systolic, and sitting systolic pressures, while heart rate increased. A number of other indices, stroke index, systemic vascular resistance, ventricular ejection time, peak flow index, ejection ratio, end diastolic index, index of contractibility and acceleration index also decreased. Overall these findings indicate that at these doses morphine decreased afterload, was negatively inotropic, positively chronotropic, had no effect on cardiac work, while maintaining left ventricular performance. In a second study I found that these effects in general were not antagonised by naloxone. Using occlusion plethysmograph and intra arteriolar morphine infusion, I further showed the existence of a peripheral action of morphine on arteries, at higher concentrations 0.6 to 3 microgram/ml, which was dose dependent. Weal, flare and itching also developed rapidly and were dose dependant. Tachyphylaxis to these effects did not develop. By using pre treatment with antihistamines and measurement of plasma histamine I showed that histamine was the prime mediator for both arteriolar and skin effects. The peripheral site of action is likely to be mediated via mast cell release of histamine from arteriolar surrounding supporting tissues, and this effect influences vascular tone in man. The arteriolar effects were antagonised by LNMMA, indicating that nitric oxide release is probably caused by histamine. High concentrations of morphine induce anaphylactoid reactions. The novel observations in this thesis explain this phenomenon and may clarify the pathophysiology of opioid-induced non-cardiac pulmonary oedema, and anaphylactoid reactions. If fluid shifts occur elsewhere in the body this may contribute to hypovolemia in shock, since endogenous opioids are thought to have a role in this situation. These findings suggest that Hi and H2 blockers should be studied in the management of patients with opioid-induced non-cardiac pulmonary oedema, and those receiving high doses of morphine such as in surgery and acute pain. The effects of Ht and H2 blockers in opioid overdose should also be investigated.
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24

Davis, Danisha Marie, Suman Dalal, Connor James, Cerrone R. Foster, and Krishna Singh. "The Role of Osteopontin in Extracellular Matrix Remodeling Following Chronic Sympathetic Stimulation in The Aging Heart." Digital Commons @ East Tennessee State University, 2019. https://dc.etsu.edu/asrf/2019/schedule/122.

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Cardiovascular disease (CVD) is the leading cause of death in the United States. A common feature in most cardiac pathologies is the dysregulation of beta-adrenergic receptors (β-AR) and changes in the extracellular matrix (ECM). The ECM maintains strength and normal organization of cardiac tissue, while fibrosis (connective tissue scarring) is necessary for repair of damaged cardiac tissue. However, the dysregulation of the ECM leads to a number of cardiac disease pathologies. Osteopontin (OPN) is a protein with diverse biological functions in regulating the ECM such as bone resorption and calcification, wound healing, cell adhesion, cell survival, and apoptosis. OPN is expressed at low levels in the heart but increases with injury by promoting collagen synthesis, cardiac fibroblast growth, and adhesions to ECM proteins. Furthermore, as the heart ages, increases in ECM reorganization leads to cardiac damage and failure. Several studies have examined the role of OPN in the heart, but to date, no studies exist on the role of OPN in response to β-AR signaling and cardiac remodeling or the role that aging plays in this response. The goal of this study was to examine the effects of OPN on cardiac ECM remodeling following chronic beta-adrenergic stimulation. We proposed that OPN expression increases cardiac remodeling and dysfunction following ISO treatment in the aging heart evidenced by increased fibrosis. For this study, young (4 months) and middle age (14 months) mice with (WT) and without (KO) the OPN gene were treated with isoproterenol (ISO) for 28 days. Echocardiography was used to assess cardiac function. Mice were euthanized, and the hearts were analyzed for fibrosis using Masson’s Trichrome Staining. Results showed ISO increased fibrosis in the WT-ISO, but not KO-ISO compared to the respective controls (SHAM, no ISO treatment) for the middle age mice (p≤0.05). Furthermore, the aged WT-ISO group exhibited a 3-fold increase in fibrosis compared to the young WT-ISO group. Results from echocardiography will be analyzed and we expect to see compromised cardiac function in the WT-ISO groups compared to KO-ISO groups. OPN is currently being examined as a potential biomarker in heart failure. The results from this study will provide new insight on changes in the cardiac vasculature in the aging heart following injury and the role OPN plays in this process.
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25

Ye, Yanping. "Designing New Drugs to Treat Cardiac Arrhythmia." PDXScholar, 2012. https://pdxscholar.library.pdx.edu/open_access_etds/638.

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Heart failure resulting from different forms of cardiomyopathy is defined as the inability of the heart to pump sufficient blood to meet the body's metabolic demands. It is a major disease burden worldwide and the statistics show that 50% of the people who have the heart failure will eventually die from sudden cardiac death (SCD) associated with an arrhythmia. The central cause of disability and SCD is because of ventricular arrhythmias. Genetic mutations and acquired modifications to RyR2, the calcium release channel from sarcoplasmic reticulum, can increase the pathologic SR Ca2+ leak during diastole, which leads to defects in SR calcium handling and causes ventricular arrhythmias. The mechanism of RyR2 dysfunction includes abnormal phosphorylation, disrupted interaction with regulatory proteins and ions, or altered RyR2 domain interactions. Many pharmacological strategies have shown promising prospects to modulate the RyR2 as a therapy for treating cardiac arrhythmias. Here, we are trying to establish a novel approach to designing new drugs to treat heart failure and cardiac arrhythmias. Previously, we demonstrated that all pharmacological inhibitors of RyR channels are electron donors while all activators of RyR channels are electron acceptors. This was the first demonstration that an exchange of electrons was a common molecular mechanism involved in modifying the function of the RyR. Moreover, we found that there is a strong correlation between the strength of the electron donor/acceptor, and its potency as a channel inhibitor/activator, which could serve as a basis and direction for developing new drugs targeting the RyR. In this study, two new potent RyR inhibitors, 4-methoxy-3-methyl phenol (4-MmC) and the 1,3 dioxole derivative of K201, were synthesized which are derivatives of the known RyR modulators, 4-chloro-3-methyl phenol (4-CmC) and K201. The ability of K201, 1,3 dioxole derivative of K201 and 4-MmC to inhibit the cardiac calcium channel is examined and compared at the single channel level. All of these compounds inhibited the channel activity at low micromolar concentrations or sub-micromolar concentrations.
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26

Couto, Gisele Kruger. "Avaliação temporal da função vascular em aorta de camundongos com deleção dos receptores a2A e a2BC adrenérgicos." Universidade de São Paulo, 2007. http://www.teses.usp.br/teses/disponiveis/42/42137/tde-01112007-155353/.

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Este estudo avaliou a função vascular em anéis de aorta e no leito vascular mesentérico (LVM) de camundongos com deleção dos receptores a2A e a2Cadrenérgicos (KO) com 3, 5 e 7 meses, os quais apresentam uma hiperatividade simpática acompanhada de cardiomiopatia. Os KO apresentaram um aumento da freqüência cardíaca em todos os grupos avaliados, e hipertrofia ventricular esquerda aos 5 e 7 meses. Na aorta, o relaxamento dependente (acetilcolina) e independente (nitroprussiato de sódio) do endotélio e da via font face=\"symbol\">a-adrenérgica (isoproterenol), assim como a contração (fenilefrina e serotonina) e a mobilização de Ca2+ não foram alterados nos KO aos 3, 5 e 7 meses. Nos KO aos 3 meses, o relaxamento mediado pelos receptores ?2-adrenérgicos (clonidina) foi reduzido. Tanto a contração (noradrenalina) como o relaxamento (acetilcolina) no LVM dos KO aos 7 meses não foi alterado. Assim, sugere-se que os vasos arteriais parecem ser menos sensíveis do que o coração aos efeitos crônicos da hiperatividade simpática nos camundongos com deleção dos receptores a2A e a2C adrenérgicos.
This study assed the vascular function in aortic rings and in mesenteric vascular bed (MVB) from mice with disruption of a2A and a2Cadrenoceptors (KO) with 3, 5 and 7 months of age, that present sympathetic hyperactivity associated with cardiomyopathy. Heart rate was increased in all KO groups, and left ventricular hypertrophy was observed only in 5 and 7 month-old KO. There are no changes in the relaxation induced by acetylcholine (ACh), sodium nitroprusside and isoproterenol in aortic rings from all groups. In addition, the contraction induced by phenylephrine and serotonin, and Ca2+ handling did not change. However, in aorta from 3 month-old KO the relaxation induced by clonidine (a2-adrenergic agonist) was reduced. In MVB from 7 month-old KO, neither the contraction (noradrenaline) nor relaxation (ACh) was modified. The results suggest that arterial vessel has been more resistant than heart to chronic effects induced by sympathetic hyperactivity observed in mice with disruption oa2A and a2C-adrenoceptors.
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27

Le, Nhut Minh Pham. "Activation of GABAA and 5HT1A receptors in the raphe pallidus abolish the cardiovascular responses to stress In conscious rats /." Full-text of dissertation on the Internet (820.97 KB), 2010. http://www.lib.jmu.edu/general/etd/2010/masters/lenp/lenp_masters_04-21-2010.pdf.

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28

Cañes, Esteve Laia. "El receptor nuclear NOR-1 en el remodelado cardiovascular: análisis de mecanismos fisiopatológicos y validación de nuevos modelos animales de utilidad preclínica." Doctoral thesis, Universitat de Barcelona, 2021. http://hdl.handle.net/10803/673943.

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Actualmente no se dispone de fármacos eficaces ni de modelos animales adecuados para estudiar el aneurisma de la aorta abdominal (AAA) ni la hipertrofia cardiaca, patologías con una elevada morbi-mortalidad. La expresión del receptor nuclear NOR-1 es elevada en el miocardio y aumenta en la aorta de pacientes con AAA. Animales modificados genéticamente para este receptor podrían ser útiles para estudiar los mecanismos de estas enfermedades y para realizar ensayos preclínicos de potenciales terapias. Estudios ecocardiográficos de nuestro grupo habían mostrado que la angiotensina II (AngII) induce dilatación aórtica tanto en un ratón que sobreexpresa NOR-1 humano (hNOR-1) preferentemente en la pared vascular y el miocardio (TgNOR-1) como en el que la expresión de hNOR-1 se dirige células musculares (TgNOR1CMLV). También se observó que los ratones TgNOR-1 desarrollan hipertrofia cardíaca en respuesta a sobrecarga de presión, y que ambos podrían ser útiles como modelos preclínicos ya que la doxiciclina prevenía la formación de aneurismas inducidos por AngII. En el presente trabajo hemos profundizado en los mecanismos celulares y moleculares por los que la transgénesis de NOR-1 predispone a la formación de AAA. En respuesta a AngII en la pared vascular de los animales transgénicos se producen más roturas de fibras elásticas y un mayor aumento de la actividad MMP, del infiltrado inflamatorio y del estrés oxidativo que en los animales control. En estos animales la doxiciclina previno la formación de aneurismas inducidos por AngII a través de la reducción del remodelado vascular, la actividad MMP, la inflamación y el estrés oxidativo. El análisis del patrón de expresión diferencial en respuesta a AngII en la aorta abdominal de ratones TgNOR1CMLV y controles mediante microarrays identificó 1512 genes regulados diferencialmente y el análisis de vías (GSEA; Gene Set Enrichment Analysis) determinó la regulación diferencial de procesos biológicos, relacionados con inflamación, ciclo celular, citoesqueleto, diferenciación de célula muscular y activación simpática. Confirmamos que en respuesta a la AngII la transgénesis de NOR-1 se asocia a la inducción de genes implicados en la síntesis y transporte de catecolaminas, entre ellos la tirosina hidroxilasa (TH), enzima limitante de esta vía. Su expresión se incrementó de manera significativa en el AAA humano en el que la TH se localiza no sólo en las terminaciones nerviosas, sino también en células inflamatorias y en menor medida en CMLV. Un perfil similar se detectó en el ratón TgNOR1CMLV y en el modelo clásico de AAA (ratón deficiente en apolipoproteína E (ApoE-/-) infundido con AngII). Destacar que la inhibición específica de la TH mediante α-Metil-DL-tirosina (AMPT), previno el desarrollo de AAA en ambos modelos reduciendo el remodelado vascular, la inflamación y el estrés oxidativo. Por tanto, se propone a la TH como una nueva diana farmacológica en el AAA. En relación con la hipertrofia cardíaca. Los cardiomiocitos de los ratones TgNOR-1 son de mayor tamaño que los controles y cuando se estimulan eléctricamente experimentan mayor acortamiento que éstos. A su vez, la transgénesis de NOR-1 en cardiofibroblastos aumentó la expresión de marcadores del cambio fenotípico fibroblasto/miofibroblasto. Estos animales presentaban un agravamiento de la hipertrofia cardiaca asociada a la edad sin alteración de la función sistólica. Análogamente, confirmamos la mayor predisposición de los ratones transgénicos a la hipertrofia cardiaca inducida por AngII, con una hipertrofia concéntrica más acentuada que los ratones control, un aumento compensatorio de la función sistólica y una exacerbada respuesta inflamatoria y fibrótica. De hecho, la sobreexpresión de NOR-1 incrementó la deposición y el entrecruzamiento de las fibras de colágeno y la expresión de marcadores fibróticos, como la lisil oxidasa like 2 (LOXL2). Asimismo, la transgénesis de NOR-1 potenció la inducción de marcadores de hipertrofia cardíaca causada por la AngII. Nuestros resultados indican que en los ratones transgénicos existe una mayor expresión basal de Myh7 y de Loxl2 y mediante ensayos de actividad transcripcional demostramos que NOR-1 regula directamente la expresión de estos genes. Estos resultados sugieren que NOR-1 está implicado en el complejo programa transcripcional que lleva a la hipertrofia hipertensiva.
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29

Smith, Frank Melvin. "Arterial baroreceptor control of the circulation during forced dives in ducks (Anas Platyrhynchos var.)." Thesis, University of British Columbia, 1987. http://hdl.handle.net/2429/27533.

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When dabbling ducks are involuntarily submerged, arterial vasoconstriction produces a large increase in the peripheral resistance to blood flow which is balanced by a decrease in output of the heart, and arterial blood pressure is maintained. Arterial baroreceptors sense systemic blood pressure, and provide the afferent information to the baroreflex for pressure regulation. The effector limbs of the baroreflex are the same as those involved in the diving responses, and the baroreceptors are likely to be important in the integration of the cardiovascular responses to diving. The purpose of this study was to investigate the role of the arterial baroreceptors in maintaining blood pressure during diving, and in the initiation and maintenance of the diving responses. Baroreceptor function was studied by diving ducks at various times after barodenervation, and by electrically stimulating the central end of one baroreceptor nerve in baroreceptor-denervated animals to simulate a controlled baroreceptor input before and during submersion. Intact baroreceptor innervation was not necessary for the development of peripheral vasoconstriction, but loss of the baroreceptors modified the cardiac response to submersion by impairing the vagally mediated bradycardia. There was no effect of baroreceptor nerve stimulation on peripheral resistance during diving, and the baroreflex operated via the heart rate in modulating blood pressure early in the dive. Later in the dive, stimulation was ineffective in altering either heart rate or blood pressue. Strong chemoreceptor drive results from decreased blood oxygen and increased carbon dioxide levels in the dive, and the results of experiments to determine the mechanism of baroreflex attenuation showed that an interaction between chemoreceptor and baroreceptor inputs may be at least partly responsible for reducing baroreflex effectiveness. The main conclusion from this work is that the arterial baroreceptors contribute to the diving responses through modulation of heart rate, to help balance the fall in cardiac output against the baroreceptor-independent peripheral vasoconstriction in the first minute of forced dives.
Science, Faculty of
Zoology, Department of
Graduate
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30

Skogsberg, Josefin. "PPAR delta : its role in cholesterol metabolism /." Stockholm, 2003. http://diss.kib.ki.se/2003/91-7349-604-9.

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31

Salo, Paul David. "Protein prenylation inhibitors reveal a novel role for rhoa and rhoc in trafficking of g protein-coupled receptors through recycling endosomes." Diss., Atlanta, Ga. : Georgia Institute of Technology, 2007. http://hdl.handle.net/1853/26711.

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Thesis (Ph. D.)--Chemistry and Biochemistry, Georgia Institute of Technology, 2008.
Committee Co-Chair: Hud, Nicholas; Committee Co-Chair: Radhakrishna, Harish; Committee Member: Doyle, Donald; Committee Member: Fahrni, Christoph; Committee Member: McCarty, Nael. Part of the SMARTech Electronic Thesis and Dissertation Collection.
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32

Morais, Kátia Luciano Pereira [UNIFESP]. "A diversidade estrutural de peptídeos potenciadores da bradicinina da Bothrops jararaca (Bj-BPPs) proporciona ações sinérgicas no sistema cardiovascular." Universidade Federal de São Paulo (UNIFESP), 2010. http://repositorio.unifesp.br/handle/11600/8814.

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Nosso laboratório mostrou que um único gene codifica um precursor protêico, cujo processamento gera o peptídeo natriurético tipo C (CNP) e uma variedade de peptídeos ricos em prolina, conhecidos como peptideos potenciadores da bradicinina ou BPPs. Com pequenas diferenças, esse precursor é expresso na glândula do veneno e na região neuro-endócrina do cérebro da Bothrops jararaca. Todos os produtos desse processamento têm como característica comum sua ação sob o sistema cardiovascular, levando à redução da pressão arterial e da frequência cardíaca. Esse fato intrigante levou-nos a questionar se esses diferentes peptídeos teriam mecanismo de ação semelhante. Surpreendentemente, esse trabalho mostrou que a resposta é negativa embora ainda não possamos explicar detalhadamente como cada um desses peptídeos atua no complexo mecanismo responsável pelo tônus vascular e pela frequência cardíaca. Historicamente, a demonstração de que os peptídeos potenciadores da bradicinina da Bothrops jararaca (Bj-BPPs) eram inibidores naturais da enzima conversora de angiotensina (ECA) teve ampla repercussão médica. Essa inibição parecia explicar a forte ação anti-hipertensiva desses peptídeos, dai servirem de modelo estrutural para o desenvolvimento de um inibidor sítio-dirigido, o Captopril, medicamento mundialmente utilizado para o tratamento da hipertensão arterial sistêmica humana. Contudo, recentes evidências experimentais sugerem que a atividade anti-hipertensiva dos Bj-BPPs não está relacionada somente com a inibição da ECA. Nosso grupo demonstrou para o Bj-BPP-10c que sua ação anti-hipertensiva se deve à ativação da geração de L-arginina, essencial para produção de óxido nítrico, potente vasodilatador, bem como pela regulação do barorreflexo arterial e pela sinalização de cálcio intracelular, ações que contribuem para a produção de NO em células endoteliais e neurais. Outros Bj-BPPs derivados do mesmo precursor foram aqui analizados. Demonstramos que o mecanismo de ação do Bj-BPP-5a envolve receptores B2 da bradicinina, o receptor muscarínico do subtipo M1 e a produção de NO. Curiosamente, o Bj-BPP-9a que serviu de modelo para a síntese do Captopril, parece atuar predominantemente como um clássico inibidor da ECA. O Bj-BPP-11e deve ter ação num receptor de membrana, assim explicando seus efeitos sobre parâmetros cardiovasculares. O mecanismo de ação do Bj-BPP-12b poderia ser explicado pela potenciação da BK e/ou pela inbição da ECA e do Bj-BPP-13a por ação em receptor muscarínico do subtipo M3 e sobre a ASS. Adicionalmente, o presente trabalho mostrou, pela primeira vez na área de toxinologia, que toxinas de serpentes já se valem do recurso bem conhecido na geração de hormônio-peptídeos em mamíferos, isto é, utilizam o processamento de uma poliproteina para gerarem peptídeos de ação sinérgica.
Our laboratory has shown that one gene codes for the protein precursor that yields the natriuretic peptide type C (CNP) after having been processed, along with a variety of proline-rich peptides, known as bradykinin-potentiating peptides or BPPs. Showing little differences, this precursor is expressed in the venom gland and the neuroendocrine region of the Bothrops jararaca brain. All processing products have in common that they act on the cardiovascular system, lowering arterial blood pressure and heart frequency. This intriguing fact led us to question whether the different peptides display similar mechanisms of action. Surprisingly, the present study showed that the answer is negative, although we cannot, at the present time, explain in full detail how each peptide acts in the complex mechanism, responsible for vascular tonus and cardiac frequency. Historically, the demonstration that the Bradykinin-Potentiating Peptides from Bothrops jararaca (Bj-BPPs) were natural inhibitors of the angiotensin converting enzyme (ACE) had a wide medical impact. In fact, this inhibition seemed to fully explain the strong anti-hypertensive action of these peptides, therefore being employed as structural models for the development of a site-directed inhibitor, Captopril, a drug used worldwide for the treatment of systemic human arterial hypertension. Recent experimental evidences, however, suggest that the anti-hypertensive activity of the Bj-BPPs is not due exclusively to the inhibition of the ACE. Our group demonstrated that the antihypertensive action of Bj-BPP-10c, for instance, is due to the activation of L-arginine generation, which is essential for NO production, a potent vasodilator. Moreover, it also regulates the arterial baroreflex and intracellular calcium signaling, which contribute to NO production in endothelial and neuronal cells. In the present work we studied the mechanism of action of other Bj-BPPs found in the above mentioned precursor. We showed that the mechanism of action of Bj-BPP-5a involves bradykinin B2 receptor, the muscarinic receptor, subtype M1, and NO production. Bj-BPP-11e probably acts on a membrane receptor, thereby explaining its effects on cardiovascular parameters. The mechanism of action of Bj-BPP-12b might be explained by Bk potentiation and/or by ACE inhibition and Bj- BPP-13a action on by muscarinic receptor subtype M3 and the ASS. Interestingly, Bj-BPP-9a, which was the model molecule for the synthesis of Captopril, seems to act predominantly as a classic ACE inhibitor. Beside the pharmacological interest, our work also revealed, for the first time, that snake toxins also employ the well-known strategy in hormone-peptide generation, that is, they use the processing of a polyprotein to generate peptides which display a synergistic action.
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33

Belcher, Pamela Elizabeth. "Role of toll-like receptors in immune and cardiovascular responses to pattern associated molecular patterns of gram-positive and gram-negative bacteria." Thesis, Imperial College London, 2007. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.479166.

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Santos, Andreza Oliveira dos [UNIFESP]. "Relação entre os títulos de anticorpos anti LDLox e marcadores do risco cardiovascular." Universidade Federal de São Paulo (UNIFESP), 2008. http://repositorio.unifesp.br/handle/11600/10030.

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Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)
Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)
Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)
Objetivos: As lipoproteínas oxidadas e os anticorpos anti-LDL oxidada (anti-LDLox) têm sido detectados no plasma e em lesões ateroscleróticas em humanos. No entanto, o papel destes autoanticorpos na proteção vascular ou na patogênese das síndromes coronarianas agudas (SCA) permanece não elucidado. Nós examinamos a relação entre os títulos de IgG humana anti-LDLox com marcadores de risco para a doença cardiovascular. Métodos: Títulos de autoanticorpos anti-LDLox foram mensurados em indivíduos portadores de hipertensão arterial em estágio 1 (n=94), sem outros fatores de risco, e em indivíduos com síndrome metabólica após recente síndrome coronariana aguda (n=116). Os autoanticorpos contra a LDL oxidada pelo cobre foram avaliados por ELISA. Resultados: pacientes com hipertensão arterial apresentaram menor índice de massa corpórea e circunferência abdominal, maiores níveis de pressão arterial sistólica e diastólica quando comparados aos portadores de SCA (p<0,001). O HDL-C e a Apo A1 foram maiores, enquanto os triglicérides e a Apo B foram menores nos pacientes do grupo hipertensão em estágio 1 (p<0,0001). Os títulos de anticorpos anti-LDLox foram maiores no grupo hipertensão comparados aos do grupo SCA, e os hipertensos do primeiro grupo apresentaram níveis de PCR menores do que indivíduos com SCA (p<0,0001). A análise conjunta de ambos os grupos mostrou, em análise univariada, significante correlação inversa para a PCR (r=-0,284), IMC (r=-0,256), circumferência abdominal (r=-0,368), apo B (r=-0,191) e glicemia (r=-0,303) e correlações positivas entre pressão arterial sistólica e diastólica (r=0,319 e r=0,167, respectivamente), HDL-C e Apo A1 (r=0,224 e r=0,257, respectivamente), com os títulos de anticorpos anti-LDLox (p<0,02). Regressão linear múltipla mostrou que a PCRas, glicemia e circunferência abdominal permaneceram independente e negativamente associados com os títulos de anticorpos anti-LDLox. Conclusões: nossos resultados sugerem que os títulos baixos de anticorpos circulantes anti-LDLox possam estar associados com maior risco cardiovascular.
Objectives: Oxidized lipoproteins and antibodies anti-oxidized LDL (anti-oxLDL) have been detected in human plasma and in atherosclerotic lesions. However, the role of these autoantibodies in the maintenance of health or in the pathogenesis of acute coronary syndromes (ACS) remains unclear. We examined the relationship of human IgG antibodies anti- ox LDL with cardiovascular disease risk markers. Methods: Titers of human anti-oxLDL were measured in hypertensive subjects in stage 1 (n=94) without other risk factors, and in individuals with metabolic syndrome after recent acute coronary syndrome (n=116). Autoantibodies against copper ion oxidized LDL were measured by ELISA. Results: Hipertensive patients presented lower BMI, waist circunference, higher blood pressure levels than those with ACS (p<0.001). HDL-C and Apo A1 were higher, whereas triglycerides and Apo B were lower in those with hypertension stage 1 (p<0.0001). Anti-oxLDL titers were higher in hypertensive patients compared to those with acute coronary syndromes, and hypertensive patients presented lower hs-CRP than those with ACS (p<0.0001). Taken into account both populations, univariate analysis showed small, but significant inverse correlations between the hs-CRP (r=-0.284), BMI (r=-0.256), waist circunference (r=-0.368), apo B (r= -0.191), and blood glucose (r= - 0.303) and positive correlations between systolic and diastolic blood pressure (r=0.319 and r=0.167, respectively), HDL-C and Apo A1 (r=0.224 and r=0.257, respectively), with anti-ox LDL titers (p<0.02). After multiple linear regression, hs-CRP, fasting glycemia and waist circunference remained independently associated with anti-oxLDL. Conclusions: Our results suggest that low titers of circulating anti-oxLDL antibodies may be associated with increased cardiovascular risk.
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35

Dornan, Thomas J. "Antioxidant Anthocyanidins and Calcium Transport Modulation of the Ryanodine Receptor of Skeletal Muscle (RyR1)." PDXScholar, 2011. https://pdxscholar.library.pdx.edu/open_access_etds/319.

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Cardiovascular disease (CVD) claims more lives than any other disease in the world. Although numerous biological pathways share the blame, ventricular tachyarrhythmia (VT) is estimated to account for ~25% of all CVD deaths. A complete understanding of the molecular mechanisms underlying VT is unknown but recent studies have linked VT to improper calcium handling in the heart (canine). The principle calcium regulator in the muscle cell is the calcium ion release channel (aka RyR). Numerous endogenous and exogenous compounds can affect the way the RyR regulates calcium. In particular, abnormal levels of oxidants (reactive oxygen species) can oxidize critical thiol groups on the RyR and modulate its activity. Interestingly, high levels of oxidants are also associated with numerous bodily disease states including cancers, muscle fatigue/failure, and CVD. In this thesis, two important dietary antioxidant compounds, the anthocyanidins pelargonidin and delphinidin, are evaluated for their effects on regulating the transport of calcium through the calcium release channel (RyR1) of the sarcoplasmic reticulum of skeletal muscle. Pelargonidin and delphinidin are structurally similar with delphinidin only differing from pelargonidin by the addition of two hydroxyl groups. Both compounds undergo time dependent structural changes in aqueous solutions at physiological pH and a mixture of more than four structures of each compound can be present in solution simultaneously. Pelargonidin and delphinidin show distinct differences in their calcium flux regulating effect on the RyR1. Delphinidin stimulates calcium flux and RyR1 activity where as pelargonidin can cause both inhibition and stimulation of the RyR1. The strength of stimulation and inhibition of calcium transport through the RyR by delphinidin and pelargonidin may be attributed to the structural and chemical changes in those compounds that occur in solutions near physiological pH and the subsequent chemical characteristics of the diverse set of structures that are simultaneously present in solution.
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36

Abdallah, Dina. "Fonctions de la phospholipase D et des récepteurs de la prostaglandine PGE2 durant la maturation des ostéoblastes, le processus de la minéralisation physiologique et la calcification cardiovasculaire." Thesis, Lyon 1, 2014. http://www.theses.fr/2014LYO10152/document.

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Le métabolisme lipidique affecte la maturation et la différenciation des cellules osseuses. L'objectif de ma thèse est d'approfondir deux aspects du métabolisme lipidique mal connus, soit les actions de la phospholipase D (PLD) et celles des récepteurs de prostaglandine PGE2 pendant la différenciation des cellules. Une lignée humaine, les Saos-2 et les ostéoblastes primaires issus de calvaria de souriceaux ont servi de modèles cellulaires de la minéralisation physiologique. La culture d'aorte ex vivo sous des conditions d'hyperphosphatémie a été utilisée pour reproduire la calcification de l'aorte qui est un modèle ex vivo de calcification cardiovasculaire (CCV). Nous avons montré que l'expression et l'activité de la PLD augmentent dans les Saos-2 et les ostéoblastes primaires au bout du 5ème jour de la différenciation tandis qu'elles s'accroissent au bout du 6ème jour de traitement de l'aorte dans un milieu d'hyperphosphatémie. Les inhibiteurs de PLD diminuent l'activité de phosphatase alcaline (TNAP) dans les ostéoblastes et dans l'aorte calcifiée tandis que la surexpression de la PLD1 dans les Saos-2 l'augmente. Dans une deuxième partie de ce travail, nous avons suivi la variation d'expression des récepteurs de PGE2 au cours de la maturation des Saos-2. L'expression du gène EP3 augmente au stade tardif de la minéralisation tandis que celle d'EP4 diminue. Pour conclure, ces résultats indiquent que l'activité de la PLD en affectant l'activité de la TNAP pourrait moduler finement la minéralisation physiologique et la CCV et que la minéralisation s'accompagne d'un changement d'expression des récepteurs de PGE2, dans les Saos-2
Lipid metabolism affects the maturation and the differentiation of bone cells. The aim of my PhD thesis is to explore two unknown sides of lipid metabolism which are the actions of phospholipase D (PLD) and those of prostaglandin PGE2 receptors during cell differentiation. Human lineage, Saos-2 cells and primary osteoblasts from calvaria of mice were used as cellular models of physiological mineralization. The ex vivo aorta culture under hyperphosphatemia conditions has been used to reproduce the calcification of the aorta, which is an ex vivo model of cardiovascular calcification (CVC). We showed that the expression and the activity of PLD increased in Saos-2 and primary osteoblasts after the fifth day of differentiation while in the aorta under hyperphosphatemia condition, PLD activity increased at the end of the sixth day. PLD inhibitors decreased the activity of alkaline phosphatase (TNAP) in osteoblasts and in calcified aorta while the overexpression of PLD1 in the Saos-2 increased it. In the second part of this work, we monitored the variation of the expression of PGE2 receptors during the maturation of Saos-2 cells. The EP3 gene expression increased in the late stage of the mineralization while that of EP4 decreased. In conclusion, these results indicated that the PLD activity by affecting the activity of TNAP could modulate the physiological mineralization and CVC. We showed that the mineralization is dependent of the change of the expression of PGE2 receptors in Saos-2 cells
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37

Konrad, David. "Cardiac function in experimental septic and non-septic conditions with special reference to the endothelin system /." Stockholm, 2006. http://diss.kib.ki.se/2006/91-7140-984-X/.

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38

Gao, Detao. "Structural basis for the recognition of oxidized phospholipids in oxidized low density lipoproteins by class B scavenger receptors CD36 and SR-BI." Case Western Reserve University School of Graduate Studies / OhioLINK, 2012. http://rave.ohiolink.edu/etdc/view?acc_num=case1313674618.

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39

Ferrán, Pérez Beatriz. "Identificación y caracterización de genes regulados por NOR-1 (Neuron-derived Orphan Receptor-1): implicación en el remodelado vascular y la diferenciación celular." Doctoral thesis, Universitat de Barcelona, 2016. http://hdl.handle.net/10803/396643.

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Las enfermedades cardiovasculares constituyen la primera causa de muerte a nivel mundial. El común denominador de las enfermedades cardiovasculares de componente isquémico es la aterosclerosis. La complicación trombótica de las placas ateroscleróticas puede ocasionar eventos clínicos como el infarto agudo de micardio o los accidentes cerebrovasculares. En la evolución de esta patología juegan un papel clave las células musculares lisas de la pared vascular, que experimentan cambios importantes en su fenotipo y en su patrón de expresión génica. En la regulación de dichos cambios participa la familia de receptores nucleares NR4A. Los receptores NR4A (NOR-1, Nurr1 y Nur77) están codificados por genes de respuesta temprana, cuya expresión se induce por estímulos mitogénicos, pro-inflamatorios y pro-aterogénicos. Nuestro grupo identificó a NOR-1 (NR4A3) como un factor de transcripción implicado en la cardiopatía isquémica y en la migración, la proliferación y la supervivencia de las células vasculares. Actualmente se desconoce la identidad de la mayoría de los genes diana de NOR-1. Los objetivos principales de este proyecto fueron la identificación de genes regulados por NOR-1 a nivel vascular y la caracterización de los mecanismos moleculares por los cuales este receptor regula su expresión. En estudios de expresión génica diferencial en células musculares lisas que sobre-expresaban los receptores NR4A, identificamos un conjunto de genes cuya expresión se modulaba significativamente. Mediante diferentes estrategias confirmamos a MYOM1, A2M y SMPX como potenciales genes diana de NOR-1. MYOM1 codifica para la miomesina 1, una proteína implicada en la contracción de las fibras musculares. La alfa-2 macroglobulina (A2M) es una anti-proteinasa de amplio espectro presente en el plasma de los vertebrados. La regulación de A2M tiene lugar mediante la unión de los receptores NR4A a un elemento NBRE presente en su promotor. Los receptores NR4A modulan la actividad de las metaloproteinasas MMP-2 y MMP-9 a través de diferentes mecanismos, entre ellos mediante la inducción de la expresión de A2M. Además evidenciamos que la A2M se expresa de forma relevante en las células musculares de la capa media de las arterias humanas. Por su parte, el gen SMPX (Small Muscle Protein X-linked) codifica para una proteína asociada al citoesqueleto que se expresa sobre todo en células de músculo esquelético y cardíaco. La regulación de SMPX por NOR-1 se produce a través de un elemento NBRE no canónico. La diferenciación de mioblastos humanos de músculo esquelético (HSMM) a miotubos incrementa la expresión y los niveles de SMPX de forma dependiente de NOR-1. El silenciamiento de NOR-1, pero no el de SMPX, inhibe el proceso de diferenciación de las células HSMM.
Cardiovascular diseases are the leading cause of death worldwide. Atherosclerosis is a common factor among ischemic cardiovascular disorders. Thrombotic complication of atherosclerotic plaques can cause clinical events such as acute myocardial infarction and strokes. Smooth muscle cells of the vascular wall play a key role in this pathology, experiencing significant changes in their phenotype and gene expression pattern during the course of the disease. The NR4A nuclear receptors family is involved in the regulation of such changes. The NR4A receptors (NOR-1, Nur77 and Nurr1) are encoded by early response genes, whose expression is induced by mitogenic, pro-inflammatory and pro-atherogenic stimuli. Our group identified NOR-1 (NR4A3) as a transcription factor involved in ischemic cardiopathy and in the migration, proliferation and survival of vascular cells. However, most of the genes targeted by NOR-1 are thus far unknown. Therefore, the main objectives of this project were to identify genes regulated by NOR-1 at the vascular level, and to characterize the molecular mechanisms by which this receptor regulates gene expression. By studying the genes differentially expressed in smooth muscle cells overexpressing NR4A receptors, we identified a set of genes whose expression was significantly shifted. Among those genes, we confirmed MYOM1, A2M and SMPX as potential targets of NOR-1. MYOM1 encodes myomesin 1, a protein involved in the contraction of muscle fibers. Alpha-2-macroglobulin (A2M) is a broad spectrum anti-proteinase present in the plasma of vertebrates. A2M is regulated by NR4A receptor, through the binding to an NBRE element present in the A2M promoter. NR4A receptors modulate the activity of MMP-2 and MMP-9 metalloproteinases through different mechanisms, including the induction of A2M expression. Furthermore, we evidence that A2M is significantly expressed in muscle cells of human arteries. Regarding SMPX (Small Muscle Protein X-linked), it encodes a cytoskeleton-associated protein, specifically expressed in skeletal and cardiac muscle cells. SMPX regulation by NOR-1 occurs through a non-canonical NBRE element. The SMPX expression is increased in a NOR-1 dependent manner during the differentiation of human skeletal myoblasts (HSMM) to myotubes. Silencing of NOR-1, but not of SMPX, inhibits the differentiation of HSMM.
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40

Wang, Xiaohui. "Role of TLRs, Hippo-YAP1 Signaling, and microRNAs in Cardiac Repair and Regeneration of Damaged myocardium During Ischemic Injury." Digital Commons @ East Tennessee State University, 2017. https://dc.etsu.edu/etd/3287.

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Cardiovascular disease is a leading cause of death in the United States. Toll-like receptor (TLR)-mediated pathways have been demonstrated to play a role in myocardial ischemia/reperfusion (I/R) injury. We and others have shown that PI3K/Akt signaling is involved in regulating cellular survival and protecting the myocardium from I/R induced injury. In this dissertation, we provide compelling evidence that miR-125b serves to “fine tune” TLR mediated NF-kB responses by repressing TNF-a and TRAF6 expression. We constructed lentiviral expressing miR-125b, delivered it into the myocardium. The data showed that delivery of lentivirus expressing miR-125b significantly reduces myocardial infarct size and improves cardiac function in I/R hearts. Mechanistic studies demonstrated that miR-125b negatively regulates TLR mediated NF-kB activation pathway by repressing TNF-a and TRAF6 expression in the myocardium. We also observed that transfection of the myocardium with lentivirus expressing miR-214 markedly attenuates I/R induced myocardial infarct size and cardiac dysfunction. We demonstrated that miR-214 activates PI3K/Akt signaling by targeting PTEN expression in the myocardium. We also investigated the role of TLR3 in neonatal heart repair and regeneration following myocardial infarction (MI). Wild type (WT) neonatal mice showed fully cardiac functional recovery and small infarct size, while TLR3 deficient mice exhibited impaired cardiac functional recovery and large infarct area after MI. Poly (I:C), a TLR3 ligand, administration significantly enhances glycolysis, YAP1 activation and the proliferation of WT neonatal cardiomyocytes. 2-deoxyglucose (2-DG), a glycolysis inhibitor treatment abolished cardiac functional recovery and YAP1 activation in neonatal mice after MI. In vitro either inhibition of glycolysis by 2-DG or inhibition of YAP1 activation prevents Poly (I:C) induced YAP1 activation and neonatal cardiomyocyte proliferation. Importantly, YAP1 activation increases miR-152 expression, leading to cardiomyocyte proliferation through suppression P27kip1 and DNMT1 expression. We conclude that microRNAs play an important role in TLR modulation induced protection against myocardial I/R injury by increasing the activation of PI3K/Akt signaling pathway, decreasing TLR/NF-kB mediated inflammatory response, and suppressing activation of apoptotic signaling following myocardial I/R injury. In addition, TLR3 is an essential for neonatal heart repair and regeneration after myocardial infarction. TLR3 modulation could be a novel strategy for heart regeneration and repair.
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41

Nistala, Pallavi. "5-HT2B Receptor-mediated Cardiac Valvulopathy." VCU Scholars Compass, 2018. https://scholarscompass.vcu.edu/etd/5689.

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5-HT2B receptor agonism causes cardiac valvulopathy, a condition characterized by thickening of the heart valves and as a result, regurgitation of blood within the heart. The anti-obesity drug fenfluramine, which was originally prescribed as an anorectic, was withdrawn from the market due to causing cardiac valvulopathy. Fenfluramine, after metabolism by N-dealkylation, produces the metabolite norfenfluramine, which acts as a more potent valvulopathogen. The same was seen with MDMA (ecstasy), a popular drug of abuse, which is metabolized by N-dealkylation to produce MDA, a more potent valvulopathogen. Glennon and co-workers. studied a series of 2,5-dimethoxy-4- substituted phenylisopropylamines (DOX type) hallucinogens and determined their affinities at the three types of 5-HT2 receptors. A high correlation was found between the affinities of these molecules at 5-HT2A and 5-HT2B receptors. Therefore, these hallucinogens have a high possibility of causing valvulopathy, which gives rise to a new class of valvulopathogens. Since certain hallucinogens have the common phenylisopropylamine structural scaffold as that of MDA and norfenfluramine, we conducted 3D-QSAR studies to identify the common structural features of these molecules that are responsible for their high affinities. We were unable to obtain a suitable CoMFA and CoMSIA model for 5-HT2B receptors, but we were able to obtain an internally and externally validated model for 5-HT2A receptor affinities which indicated the hydrophobicity of the substituent at the 4- position was essential for high affinity. Following up with this evidence, we conducted a correlation analysis for the hydrophobicity (π-value) of the 4-position substituent and found a positive correlation between the π-value and the affinity of the molecules. The same results were not observed for the volume of the substituents. We docked the molecules into the 5-HT2B receptor and successfully generated models of the putative interactions made by the DOX molecules and the receptor. In order to compare their binding modes with respect to known valvulopathogens, we also generated models for norfenfluramine and MDA. Our docking results revealed that DOX molecules bind in a more or less similar manner to valvulopathogens MDA and norfenfluramine. Ours is the first in silico model developed for the potent valvulopathogen MDA and the hallucinogenic DOX series of molecules.
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FIGUEIREDO, Ariane A. B. "Caracterizações morfofuncionais testiculares e cardíacas em camundongos knockout para receptor do LDL." Universidade José do Rosário Vellano, 2018. http://tede2.unifenas.br:8080/jspui/handle/jspui/208.

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Fundação de Amparo à Pesquisa do Estado de Minas Gerais - FAPEMIG
Coordenação de Aperfeiçoamento de Pessoal de Nível Superior - CAPES
Variations in lipids and lipoproteins are considered a risk factor for cardiovascular diseases, such as atherosclerosis. This study evaluated the effect of genetic and alimentary dyslipidemia on testicular morphofunctional characteristics and whether its relation with the cardiovascular diseases developed by hyperlipidic diets in genetically modified mice, absent LDL receptor (Ldlr-/-) and wild type mice. In addition to evaluating the replacement of testosterone in the protection of the cardiovascular system of Ldlr-/- mice fed or not with a hyperlipidic diet. In the first study, Ldlr-/- mice were selected, divided into four groups (n = 10): S: animals fed standard diet (Nuvital®) for rodents and without testosterone application; ST: animals fed standard diet (Nuvital®) for rodents and with testosterone application (0.01 ml per week); HL: animals fed a hyperlipid diet (20% total fat, 1.25% cholesterol and 0.5% cholic acid) and without testosterone application; HLT: animals fed a hyperlipid diet (20% total fat, 1.25% cholesterol and 0.5% colic) and with testosterone application (0.01 ml per week). In the analysis of the lipid profile, the mice that received hyperlipidic diets (HL and HLT) presented severe mixed dyslipidemia with increased serum levels of total cholesterol, LDL, VLDL and triglycerides, when compared to the mice of the S and ST groups. However, the HLT group showed an increase in serum HDL levels when compared to the mice in the HL group. The mice from the S and ST groups had increased serum HDL levels in relation to the other groups studied. In the second study, it was observed that the dyslipidemia generated by the LDL receptor deficiency (Ldlr-/-) has a positive relation with the increase in the production of vascular superoxide anions, increased expression of CD40 and FasL in the testis. Genetic deletion of the LDL receptor (Ldlr-/-) in mice associated with a hyperlipidic diet increased both systemic and testicular damage. In conclusion, the metabolic disorders of the lipids generated by the deletion of the LDL gene induced testicular dysfunction, by mechanisms involving oxidative stress, inflammation and apoptosis, impairing spermatogenesis and testicular steroidogenesis. It is also suggested that testosterone may indirectly cause hypertrophy of cardiomyocytes
As variações nos lipídeos e lipoproteínas são consideradas um fator de risco para doenças cardiovasculares, como a aterosclerose. Este estudo avaliou o efeito da dislipidemia genética e alimentar nas características morfofuncionais testiculares e se sua relação com as doenças cardiovasculares desenvolvidas por dietas hiperlipídicas em camundongos geneticamente modificados, ausente do receptor do LDL (Ldlr-/-) e em camundongos selvagens (wild type). Além de avaliar a reposição da testosterona na proteção do sistema cardiovascular de camundongos Ldlr-/- alimentados ou não com dieta hiperlipídica. No primeiro trabalho, foram selecionados camundongos Ldlr-/-, divididos em quatro grupos (n=10): S: animais alimentados com dieta padrão (Nuvital®) para roedores e sem aplicação de testosterona; ST: animais alimentados com dieta padrão (Nuvital®) para roedores e com aplicação de testosterona (0,01ml por semana); HL: animais alimentados com dieta hiperlipídica (20% de gordura total, 1,25% de colesterol e 0,5% de ácido cólico) e sem aplicação de testosterona; HLT: animais alimentados com dieta hiperlipídica (20% de gordura total, 1,25% de colesterol e 0,5% de ácido cólico) e com aplicação de testosterona (0,01ml por semana). Na análise do perfil lipídico, os camundongos que receberam dietas hiperlipídicas (HL e HLT) apresentaram dislipidemia mista severa com aumento dos níveis séricos do colesterol total, LDL, VLDL e triglicérides, quando comparados com os camundongos dos grupos S e ST. Contudo os camundongos dos grupos HLT apresentaram aumento nos níveis séricos de HDL quando comparados com os camundongos do grupo HL. Os camundongos do grupo S e ST apresentaram níveis séricos de HDL aumentados em relação aos demais grupos estudados. No segundo trabalho, observou-se que a dislipidemia gerada pela deficiência do receptor de LDL (Ldlr-/-) tem uma relação positiva com o aumento da produção de ânions de superóxido vascular, aumento da expressão de CD40 e FasL no testículo. A deleção genética do receptor de LDL (Ldlr-/-) em camundongos associados a uma dieta hiperlipídica aumentou o dano sistêmico e testicular. Em conclusão, os distúrbios metabólicos dos lipídeos gerados pela deleção do gene LDL induziram a disfunção testicular, por mecanismos envolvendo estresse oxidativo, inflamação e apoptose, prejudicando a espermatogênese e a esteroidogênese testicular. Sugere-se também que a testosterona possa causar indiretamente a hipertrofia de cardiomiócitos.
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43

Kheder, Murad Hasan. "The role of the equine enteroinsular axis in insulin dysregulation: In vitro mechanistic insights for disease prevention." Thesis, Queensland University of Technology, 2018. https://eprints.qut.edu.au/122879/2/Murad_Kheder_Thesis.pdf.

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Insulin dysregulation encompasses abnormalities in insulin metabolism, including hyperinsulinaemia and insulin resistance. These abnormalities cause diseases in horses and humans, including laminitis and type-2 diabetes mellitus, respectively. This project investigated the role of incretins, and their receptors, in equine insulin dysregulation, and also examined the inhibitory effect of sweet-taste receptor antagonists on intestinal glucose uptake. The project discovered that incretin action and glucose uptake can be attenuated in horses using incretin, and sweet-taste receptor, antagonists, respectively. This is a novel approach to reducing hyperinsulinaemia. Thus, these pathways should be further investigated as novel therapies for metabolic syndrome and laminitis.
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44

Revuelta, López Elena. "Implicación del Low Density Lipoprotein Receptor-Related Protein 1 (LRP1) en el remodelado vascular y cardiaco." Doctoral thesis, Universitat de Barcelona, 2015. http://hdl.handle.net/10803/326465.

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La dislipemia y la hipoxia tienen un impacto directo en el remodelado vascular y cardiaco. La isquemia cardiaca produce una disfunción generalizada del corazón caracterizada por alteraciones en el metabolismo celular y necrosis tisular, además reduce drásticamente los niveles de la bomba de calcio ATPase del retículo sarcoplásmico (SERCA2), crucial para la función cardiaca. La hipoxia incrementa la expresión del receptor LRP1 en células musculares lisas de la pared vascular humanas (hVSMCs) y cardiomiocitos, y altera la función vascular promoviendo remodelado de la matriz extracelular, cuya integridad y composición está modulada por metaloproteinasas (MMPs). La expresión y niveles extracelulares de MMP-9 pueden estar reguladas por el LRP1, aunque hoy en día las consecuencias de la alteración de la expresión del LRP1 en la expresión y la actividad de la MMP-9 son controvertidas. A su vez, se sabe que la hipoxia altera la fosforilación de la tirosin kinasa rica en prolina 2 (Pyk2), kinasa que participa en diversos procesos biológicos. Así mismo, se ha demostrado el papel fisiopatológico de la sobreexpresión del LRP1 en hVSMCs y cardiomiocitos al promover la acumulación de colesterol esterificado (CE) en la pared vascular y el miocardio. La dislipemia tiene un impacto directo en el remodelado vascular y cardiaco alterando componentes de la matriz extracelular como la elastina, pero a pesar de la gran relevancia de la elastina en el remodelado vascular y cardiaco, el efecto de la acumulación lipídica en los cardiomiocitos sobre las características de la tropoelastina (TE) no ha sido estudiado. En primera instancia el objetivo fue estudiar la implicación del receptor LRP1 en el remodelado vascular y cardiaco asociado a factores de riesgo como la hiperlipemia y condiciones fisiopatológicas como la hipoxia, tanto en hVSMCs como en cardiomiocitos HL-1, así como elucidar los mecanismos de señalización dependientes de LRP1 involucrados en el remodelado vascular y cardiaco. Nuestros resultados, publicados en el artículo "Hypoxia Induces Metalloproteinase-9 Activation and Human Vascular Smooth Muscle Cell Migration Throught Low-Density Lipoprotein Receptor-Related Protein 1-Mediated Pyk2 Phosphorylation", demostraron que la activación del eje LRP1/pPyk2/NF-113 por hipoxia es esencial para la sobreexpresión de MMP-9 y la migración de hVSMCs en situación de deficiencia de oxígeno. Además, el tratamiento con PP2 reduce la capacidad migratoria de hVSMCs sin generar un perfil pro-inflamatorio, por lo que PP2 podría ser una potencial herramienta terapéutica en la prevención del remodelado vascular y la inflamación presentes en enfermedades vasculares asociadas a hipoxia. A continuación, estudiamos los efectos de la acumulación intracelular del CE y de la hipoxia en el remodelado cardiaco. Publicados en el artículo "Cardiomyocyte intracellular cholesteryl ester accumulation promotes tropoelastin physical alteration and degradation. Role of LRP1 and CathepsinS", nuestros resultados sugieren que las lipoproteínas aterogénicas modifican las características físicas y estructurales de la TE, el CE acumulado promueve la fragmentación de la TE al incrementar los niveles proteicos de la CatS madura en cardiomiocitos. Por lo que el LRP1 favorece el remodelado cardiaco asociado a esteatosis miocárdica. Por último, en el tercer artículo "Hypoxia-driven sarcoplasmicIendoplasmic reticulum calcium ATPase 2 (SERCA2) downregulation depends on low-density lipoprotein receptor-related protein 1 (LRP1)- signalling in cardiomyocytes” observamos que mediante la activación del eje LRP1/pPyk2/ HIF-1α la hipoxia reduce los niveles de SERCA2 en cardiomiocitos, pudiendo ser este eje una potencial herramienta terapéutica para impedir la depleción de SERCA2 inducida por hipoxia, una de las alteraciones más importantes en la disfunción contráctil.
Hypoxia increases LRP1 expression in human vascular smooth muscle cells (hVSMCs) and cardiomyocytes, altering vascular function and promoting vascular remodeling through metalloproteinases (MMPs). MMP-9 expression and its extracellular levels may be regulated by LRP1. It's also demonstrated the physiopathological role of LRP1 overexpression in hVSMCs and cardiomyocytes by promoting esterified cholesterol (CE) accumulation in the vessel wall and myocardium. In the first instance the objectives were to analyze the involvement of LRP1 receptor in vascular and cardiac remodeling associated to risk factors like hyperlipidemia and pathophysiological conditions such as hypoxia, and the mechanisms involved in this effect. Our findings, published in the article "Hypoxia Induces Metalloproteinase-9 Activation and Human Vascular Smooth Muscle Cell Migration Throught Low-Density Lipoprotein Receptor-Related Protein 1-Mediated Pyk2 Phosphorylation" demonstrated that the activation of LRP1/pPyk2/ NF- KR axis by hypoxia is essential for MMP-9 overexpression and hVSMCs migration under hypoxia conditions. PP2 treatment reduces the migratory ability of hVSMCs without generating a pro-inflammatory profile, indicating that PP2 could be a potential therapeutic tool in preventing vascular remodeling and inflammation, present in vascular diseases associated with hypoxia. Next, we studied the effects of intracellular accumulation of CE and hypoxia in heart remodeling. Published in the article "Cardiomyocyte intracellular cholesteryl ester accumulation promotes tropoelastin physical alteration and degradation. Role of LRP1 and CathepsinS" our results suggested that atherogenic lipoproteins modify the physical and structural characteristics of TE. Accumulated CE promotes TE fragmentation through high levels of CatS in cardiomyocytes. Then, LRP1 promotes cardiac remodeling associated with myocardial steatosis. Finally, the third article "Hypoxia-driven sarcoplasmicIendoplasmic reticulum calcium ATPase 2 (SERCA2) downregulation depends on low-density lipoprotein receptor-related protein 1 (LRP1)-signalling in cardiomyocytes" showed how hypoxia reduces SERCA2 levels through LRP1/pPyk2/HIF-1 a axis in cardiomyocytes. This axis may be a potential therapeutic tool by preventing hypoxia-driven SERCA2 depletion, one of the most important alteration in contractile dysfunction.
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45

Tarjus, Antoine. "Implication de la Lipocaline 2 dans les effets physiopathologiques du récepteur minéralocorticoïde dans le système cardiovasculaire." Thesis, Paris 6, 2014. http://www.theses.fr/2014PA066457/document.

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Les pathologies cardiovasculaires sont la première cause de mortalité dans le monde. Parmi les mécanismes participant à ces pathologies figurent l'activation de la voie de signalisation minéralocorticoïde. Notre laboratoire a précédemment identifié la Lipocaline 2 (Lcn2) comme cible directe du complexe aldostérone/récepteur minéralocorticoïde (RM) dans le système cardiovasculaire. Lcn2, aussi appelée Neutrophil Gelatinase Associated Lipocalin (NGAL), est une protéine circulante, membre de la famille des lipocalines. Elle est décrite comme participant à l'inflammation ou comme régulant l'activité et la stabilité de la métalloprotéinase matricielle 9. L'objectif de ce travail de thèse est d'étudier l'implication possible de Lcn2 dans les effets pathologiques pro-fibrosants et pro-inflammatoires du complexe aldostérone/RM dans le système cardiovasculaire. Pour ce faire, des souris présentant une inactivation globale et constitutive de Lcn2 (KO Lcn2), ainsi que leurs contrôles, ont été soumises à un traitement mimant une sur-activation de la voie minéralocorticoïde (traitement néphrectomie-aldostérone-sel) durant 4 semaines. Ce travail a mis en évidence le rôle de Lcn2 dans le développement de la fibrose périvasculaire et l'inflammation induite par le complexe aldo/RM ainsi que dans l'augmentation de pression artérielle. En revanche, Lcn2 n'intervient pas dans la fibrose interstitielle ni dans la dysfonction vasculaire. Les mécanismes d'action de la Lipocaline 2 dans ces différents phénomènes pathologiques restent à élucider. En conclusion, les résultats obtenus montrent l’implication directe de Lcn2 dans les effets pro-fibrosants du complexe aldo/RM au niveau cardiovasculaire, suggérant une potentielle cible thérapeutique dans la fibrose cardiovasculaire
Cardiovascular diseases are the leading cause of death worldwide. Among the mechanisms involved in these pathologies, there is the activation of the mineralocorticoid signaling pathway. Our laboratory has previously identified Lipocalin 2 (Lcn2) as a direct target of the aldosterone/mineralocorticoid receptor (MR) complex in the cardiovascular system. Lcn2, also called Neutrophil Gelatinase Associated Lipocalin (NGAL), is a circulating protein, a member of the lipocalin family. It is described as being involved in inflammation or as regulating the activity and stability of matrix metallopeptidase 9. The aim of this work is to investigate the possible involvement of Lcn2 in pro-fibrotic and pro-inflammatory pathological effects of aldosterone/MR complex in the cardiovascular system. For this purpose, mice with constitutive and overall Lcn2 inactivation (Lcn2 KO) and their littermates were subjected to a treatment mimicking overactivation of the mineralocorticoid pathway (nephrectomy-aldosterone-salt treatment) during 4 weeks. This work has highlighted the role of Lcn2 in the development of perivascular fibrosis and inflammation induced by the complex aldo/MR and in the blood pressure increase. However, Lcn2 is not involved in interstitial fibrosis or vascular dysfunction. The action of Lipocalin 2 in these pathological phenomena mechanisms remains to be elucidated. In conclusion, the results show the direct involvement of Lcn2 in the pro-fibrotic effects of aldo/MR complex in the cardiovascular system, suggesting a potential therapeutic target in cardiovascular fibrosis
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46

Arkenbout, Elisabeth Karin. "TR3 nuclear orphan receptor in cardiovascular disease." [S.l. : Amsterdam : s.n.] ; Universiteit van Amsterdam [Host], 2004. http://dare.uva.nl/document/77443.

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47

Ward, Jonathan Robert. "Toll-like receptor control of cardiovascular inflammation." Thesis, University of Sheffield, 2005. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.425206.

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48

Silva, Talita de Melo e. [UNESP]. "Respostas cardiovasculares e na ingestão de água e NaCl hipertônico em ratos com doença periodontal tratados com agonista GABAA no núcleo parabraquial lateral." Universidade Estadual Paulista (UNESP), 2012. http://hdl.handle.net/11449/88607.

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Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)
Injeções no núcleo parabraquial lateral (NPBL) de muscimol, agonista de receptores GABAA, promove aumento de pressão arterial e induz ingestão de NaCl 0.3 M e água em ratos normovolêmicos, saciados e depletados de sódio. A doença periodontal é uma condição inflamatória que promove a liberação de citocinas próinflamatórias, tais como IL-6 e TNF-α e a destruição das estruturas de suporte do dente. As citocinas pró-inflamatórias podem modular a neurotransmissão GABAérgica e ativar neurônios do NPBL. Neste estudo, investigamos o efeito da ativação GABAérgica no NPBL com muscimol na ingestão de NaCl hipertônico e água e parâmetros cardiovasculares em ratos normovolêmicos, saciados e depletados pelo modelo FURO+CAP com doença periodontal. Foram utilizados ratos Wistar divididos em dois grupos: com doença periodontal induzida por ligadura (DP) e sem doença periodontal (grupo controle). Quinze (15) dias após a indução da doença periodontal em ambos os grupos foram implantadas cânulas bilaterais no NPBL. Ratos saciados controles que receberam injeções bilaterais no NPBL de muscimol tiveram aumento na ingestão...
GABAA receptor activation with muscimol in the lateral parabrachial nucleus (LPBN) induces water and hypertonic sodium chloride (NaCl) intake in rats. The purpose of this study was to investigate whether local inflammatory event, such as periodontal disease, is able to alter the effects of injections of muscimol (GABAA receptor agonist) into the LPBN on water and 0.3 M NaCl intake in fluid replete rats and in rats treated with diuretic furosemide (FURO) combined with a low dose of the angiotensin-converting enzyme inhibitor captopril (CAP) injected subcutaneously. Male Wistar rats were divided into two groups: with experimental ligature-induced periodontal disease (PD) and those without PD (control conditions). Fifteen days after application of the ligature, both groups had cannulas implanted bilaterally into the LPBN, and were given simultaneous access to water and 0.3 M NaCl intake. In fluid replete rats without PD, injections of muscimol (0.5 nmol/0.2 μl) into the LPBN induced 0.3 M NaCl intake (15.8 ± 2.4 vs. saline: 0.2 ± 0.05 ml/210 min), water intake (14.2 ± 1.2 vs. saline: 0.6 ± 0.3 ml/210 min) and pressor response (15 ± 3.3 mmHg, vs. saline: 0.6 ± 1.3 mmHg). In fluid replete rats (PD group), a decrease was observed in water intake (6.0 ± 1.4 ml/210 min), pressor response (7.5 ± 3.1 mmHg), but not in 0.3 M NaCl intake induced by muscimol. In rats with FURO + CAP-treatment (control group), injections of muscimol into the LPBN increased 0.3 M NaCl (25.9 ± 5.8 vs. saline: 5.7  1.0 ml/210 min) and water intake (19.9  1.2 vs. saline: 11.2  1.0 ml/210 min). In rats with FURO + CAP-treatment (PD group), a decrease was observed in 0.3 M NaCl intake (10.9 ± 2.9 ml/210 min) and water intake (13.4  2.3 ml/210 min) after... (Complete abstract click electronic access below)
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49

Silva, Talita de Melo e. "Respostas cardiovasculares e na ingestão de água e NaCl hipertônico em ratos com doença periodontal tratados com agonista GABAA no núcleo parabraquial lateral /." Araçatuba, 2012. http://hdl.handle.net/11449/88607.

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Orientador: João Carlos Callera
Banca: José Vanderlei Menani
Banca: Juliana Irani Fratucci De Gobbi
Resumo: Injeções no núcleo parabraquial lateral (NPBL) de muscimol, agonista de receptores GABAA, promove aumento de pressão arterial e induz ingestão de NaCl 0.3 M e água em ratos normovolêmicos, saciados e depletados de sódio. A doença periodontal é uma condição inflamatória que promove a liberação de citocinas próinflamatórias, tais como IL-6 e TNF-α e a destruição das estruturas de suporte do dente. As citocinas pró-inflamatórias podem modular a neurotransmissão GABAérgica e ativar neurônios do NPBL. Neste estudo, investigamos o efeito da ativação GABAérgica no NPBL com muscimol na ingestão de NaCl hipertônico e água e parâmetros cardiovasculares em ratos normovolêmicos, saciados e depletados pelo modelo FURO+CAP com doença periodontal. Foram utilizados ratos Wistar divididos em dois grupos: com doença periodontal induzida por ligadura (DP) e sem doença periodontal (grupo controle). Quinze (15) dias após a indução da doença periodontal em ambos os grupos foram implantadas cânulas bilaterais no NPBL. Ratos saciados controles que receberam injeções bilaterais no NPBL de muscimol tiveram aumento na ingestão... (Resumo completo, clicar acesso eletrônico abaixo)
Abstract: GABAA receptor activation with muscimol in the lateral parabrachial nucleus (LPBN) induces water and hypertonic sodium chloride (NaCl) intake in rats. The purpose of this study was to investigate whether local inflammatory event, such as periodontal disease, is able to alter the effects of injections of muscimol (GABAA receptor agonist) into the LPBN on water and 0.3 M NaCl intake in fluid replete rats and in rats treated with diuretic furosemide (FURO) combined with a low dose of the angiotensin-converting enzyme inhibitor captopril (CAP) injected subcutaneously. Male Wistar rats were divided into two groups: with experimental ligature-induced periodontal disease (PD) and those without PD (control conditions). Fifteen days after application of the ligature, both groups had cannulas implanted bilaterally into the LPBN, and were given simultaneous access to water and 0.3 M NaCl intake. In fluid replete rats without PD, injections of muscimol (0.5 nmol/0.2 μl) into the LPBN induced 0.3 M NaCl intake (15.8 ± 2.4 vs. saline: 0.2 ± 0.05 ml/210 min), water intake (14.2 ± 1.2 vs. saline: 0.6 ± 0.3 ml/210 min) and pressor response (15 ± 3.3 mmHg, vs. saline: 0.6 ± 1.3 mmHg). In fluid replete rats (PD group), a decrease was observed in water intake (6.0 ± 1.4 ml/210 min), pressor response (7.5 ± 3.1 mmHg), but not in 0.3 M NaCl intake induced by muscimol. In rats with FURO + CAP-treatment (control group), injections of muscimol into the LPBN increased 0.3 M NaCl (25.9 ± 5.8 vs. saline: 5.7  1.0 ml/210 min) and water intake (19.9  1.2 vs. saline: 11.2  1.0 ml/210 min). In rats with FURO + CAP-treatment (PD group), a decrease was observed in 0.3 M NaCl intake (10.9 ± 2.9 ml/210 min) and water intake (13.4  2.3 ml/210 min) after... (Complete abstract click electronic access below)
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50

Tikh, Eugene I. "Regulation of Contractility by Adenosine A1 and A2A Receptors in the Murine Heart: Role of Protein Phosphatase 2A: A Dissertation." eScholarship@UMMS, 2006. https://escholarship.umassmed.edu/gsbs_diss/130.

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Adenosine is a nucleoside that plays an important role in the regulation of contractility in the heart. Adenosine receptors are G-protein coupled and those implicated in regulation of contractility are presumed to act via modulating the activity of adenylyl cyclase and cAMP content of cardiomyocytes. Adenosine A1 receptors (A1R) reduce the contractile response of the myocardium to β-adrenergic stimulation. This is known as anti adrenergic action. The A2A adenosine receptor (A2AR) has the opposite effect of increasing contractile responsiveness of the myocardium. The A2AR also appears to attenuate the effects of A1R. The effects of these receptors have been primarily studied in the rat heart and with the utilization of cardiomyocyte preparations. With the increasing use of receptor knockout murine models and murine models of various pathological states, it is of importance to comprehensively study the effects of adenosine receptors on regulation of contractility in the murine heart. The following studies examine the adenosinergic regulation of myocardial contractility in isolated murine hearts. In addition, adenosinergic control of contractility is examined in hearts isolated from A2AR knockout animals. Responses to adenosinergic stimulation in murine isolated hearts are found to be comparable to those observed in the rat, with A1R exhibiting an anti adrenergic action and A2AR conversely enhancing contractility. A significant part of the A2AR effect was found to occur via inhibition of the A1R antiadrenergic action. A part of the anti adrenergic action of A1R has previously been shown to be the result of protein phosphatase 2A activation and localization to membranes. Additional experiments in the present study examine the effect of adenosinergic signaling on PP2A in myocardial extracts from wild type and A2AR knockout hearts. A2AR activation was found to decrease the activity of PP2A and enhance localization of the active enzyme to the cytosol; away from its presumed sites of action. In the A2AR knockout the response to A1R activation was enhanced compared with the wild type and basal PP2A activity was reduced. It is concluded that A2AR modulation of PP2A activity may account for the attenuation of the A1R effect by A2AR observed in the contractile studies.
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