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1
Simpkin, J. C. "Apelin : a cardioprotective adipocytokine." Thesis, University College London (University of London), 2007. http://discovery.ucl.ac.uk/1445937/.
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The epidemic of obesity has led to increased interest in its role in the pathogenesis of cardiometabolic disease. Adipose tissue, formerly regarded as purely an energy storage site, is now regarded as an important endocrine organ. It produces various peptide hormones, including the adipocytokines which are implicated in metabolic control and disease. Whilst some adipocytokines may contribute to the development of cardiovascular disease, others e.g. adiponectin, may protect against it. The recently identified ligand for the G protein coupled receptor APJ, apelin, is a unique vasoactive adipocytokine. Both apelin and APJ mRNA are highly expressed in the cardiovascular system. Apelin has been found to modulate cardiovascular function, fluid homeostasis and inflammation. To date, however, apelin has not been investigated in the context of ischemia-reperfusion and its benefits in this clinical setting are not yet established. APJ/apelin activates the cell survival cascades Akt/PKB and ERK-1/2 which are associated with the pro-survival Reperfusion Injury Salvage Kinase (RISK) pathway. Apelin also promotes mitogenesis, a feature commonly exhibited by cardioprotective agents. We, therefore, hypothesised that apelin may protect the heart via the RISK pathway in an ischemia/reperfusion (MR) model. We investigated if apelin has potential as a cardioprotective agent employing murine models of ischemia-reperfusion injury and rat cardiomyocytes, in which mitochondrial permeability transition pore (mPTP) opening was examined. Apelin- 13 was found to produce a concentration-dependent decrease in infarct size with a maximal effect being observed at 1000nM. The physiologically less active peptide, apelin-36, also reduced infarct size but to lesser extents than seen with the shorter isoform. LY294002 and U0126, inhibitors of the PI3K-Akt, p44/42, abolished the effects of apelin-13. Further evidence for the involvement of these pathways in the cardioprotective actions of apelin was obtained on Western blot analysis. Apelin-13 delayed mPTP opening which was blocked by LY294002 and MEK inhibitor 1, an alternative inhibitor of p44/42. This is the first study to demonstrate that apelin has a direct cardioprotective action involving the PI3K- Akt, and p44/42 signalling pathways.
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Daubney, J. "The cardioprotective mechanisms of dietary flavonoids." Thesis, Nottingham Trent University, 2015. http://irep.ntu.ac.uk/id/eprint/27927/.
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Mitotic rat embryonic cardiomyoblast-derived H9c2 cells are widely used as a model cardiomyocyte to study the protective mechanisms of dietary flavonoids, but they lack features of fully differentiated cardiomyocytes. Therefore, this present study aimed to investigate the cytoprotective and cytotoxic effects of the dietary flavonoids quercetin, kaempferol, myricetin and two major quercetin metabolites, quercetin-3-glucoronide and 3’-O-methylquercetin, on fully differentiated H9c2 cells for the first time. The cardiomyocyte-like phenotype of the differentiated H9c2 cells was confirmed by monitoring the expression of cardiac specific troponin T, as well as through the identification of other cardiac specific cytoskeletal markers using MALDI-TOF MS/MS. The cytoprotective effect of quercetin, kaempferol, myricetin, quercetin-3-glucoronide and 3’-O-methylquercetin against hypoxia and H2O2-induced cell death was assessed by monitoring MTT reduction and LDH release. Furthermore the effect of quercetin pre-treatment on ERK1/2, PKB, JNK and p38 MAPK phosphorylation was monitored using western blotting. It was shown that quercetin was the most potent flavonoid at inducing a protective effect, and 3’-O-methylquercetin the most potent metabolite. Using western blotting it was shown that this protective effect is most likely due to quercetin-mediated inhibition of ERK1/2, PKB, JNK and p38 MAPK. Specific inhibitors of these protein kinases did not modulate the observed cytoprotective effect, or cause significant protection alone. The cytotoxic effects of dietary flavonoids, particularly quercetin, was monitored with MTT reduction, LDH release, western blotting to monitor phosphorylation of ERK1/2, PKB, JNK and p38 MAPK and activation of caspase-3, and monitoring intracellular ROS generation with DCFDA assay. The cytotoxic effect of quercetin was shown to be linked to intracellular ROS generation, caspase-3 activation and phosphorylation of ERK1/2, PKB, JNK and p38 MAPK. MALDI-TOF MS for the first time identified several proteins associated with the flavonoid-mediated cytoprotective effect and flavonoid pre-treatment in differentiated H9c2 cells. Most were shown to be linked to the regulation of MAPK and PI3K cell signalling pathways. This present study for the first time demonstrates the cytoprotective and cytotoxic effects of flavonoids on differentiated H9c2 cells, and has identified novel proteins associated with the cytoprotective effect.
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Muraski, John A. "The cardioprotective effects of Pim-1 kinase." Diss., Connect to a 24 p. preview or request complete full text in PDF format. Access restricted to UC campuses, 2007. http://wwwlib.umi.com/cr/ucsd/fullcit?p3310011.
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Thesis (Ph. D.)--University of California, San Diego and San Diego State University, 2007.Title from first page of PDF file (viewed September 4, 2007). Available via ProQuest Digital Dissertations. Vita. Includes bibliographical references (p. 90-103).
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Hassan, Lobna Mohammed Saber Abdel. "Intracellular mechanisms of action of cardioprotective agents." Thesis, University of Sunderland, 1997. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.338350.
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McCafferty, Kieran. "Novel cardioprotective strategies for the uraemic heart." Thesis, Queen Mary, University of London, 2011. http://qmro.qmul.ac.uk/xmlui/handle/123456789/8725.
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Cardiovascular disease is the leading cause of death in patients with underlying chronic kidney disease (CKD). Up to one third of patients presenting with an acute coronary syndrome have CKD stage 3-5. Outcomes following acute myocardial infarction in patients with underlying CKD remain poor. CKD patients are routinely excluded from clinical trials in novel cardioprotective strategies resulting in a paucity of prospective data on which to base guidelines for clinical practice. The aims of this work were to: • Establish and characterise two models of chronic uraemia in rodents: the subtotal nephrectomy model and the adenine diet model. • Determine the effects of underlying chronic uraemia on myocardial ischaemia tolerance. • Examine pharmacological cardioprotective strategies in the context of underlying uraemia using a PARP inhibitor • Investigate the cardioprotective effects of ischaemic conditioning in the context of uraemia. Ischaemic preconditioning and postconditioning protocols were used in both uraemic and non-uraemic animals in a model of acute myocardial infarction. • Preliminary work, using standard molecular biological techniques, was carried out in order to confirm the putative survival pathways responsible for the effect of preconditioning. • Investigate the effect of combining early and late remote ischaemic preconditioning to identify whether summation of these strategies could provide additional tissue protection in a model of acute kidney injury. The results demonstrate that both models develop a uraemic phenotype. Subtotal nephrectomy animals exhibit reduced ischaemia tolerance. PARP inhibition as a pharmacological post conditioning agent was shown to be ineffective at conferring tissue protection, whereas both ischaemic preconditioning and postconditioning were effective cytoprotective strategies in both non-uraemic and uraemic animals. Furthermore, additional benefit was seen when early and late remote preconditioning were summated in a rodent model of acute kidney injury. This work provides a basis for future clinical trials in cardioprotection in the context of underlying CKD.
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Poolman, Toryn. "Investigations into the cardioprotective properties of resveratrol." Thesis, University of Leicester, 2004. http://hdl.handle.net/2381/29695.
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In this study the ability of resveratrol to inhibit the activation of the monocyte respiratory burst was investigated.;Differentiated U937 (dU937) cells were pre-treated with resveratrol before stimulation with f-met-leu-phe (fMLP), phorbol 12-myristate-13-acetate (PMA) or arachidonic acid (AA). The extra-cellular and total production of reactive oxygen species (ROS) were measured by isoluminol and luminol chemiluminescence (CL). Superoxide production was measured using lucigenin. Resveratrol was found to inhibit ROS production induced by all three stimuli. Measurement of ROS production was also confirmed using with two used, 2',7'-dichlorofluorescein (DCF) and dihydrorhodamine (DHR). Again resveratrol inhibited both responses. There were significant between the inhibitory effects of resveratrol on peroxidase-dependent (isoluminol, luminol, DCF and DHR) and independent (lucigenin- ROS measuring principles. Moreover, resveratrol was found to be oxidised by the horseradish peroxidase/hydrogen peroxide system.;The cell signal transduction pathways activated by fMLP, PMA and AA were investigated. Only fMLP was found to activate phosphatidylinositol-3-kinase (PI3K) and Akt, using specific inhibitors of both kinases. Resveratrol inhibited PI3K activity with little direct effect on other kinases shown to regulate the respiratory burst, including Akt, extra-cellular regulated protein kinase (ERK); and protein kinase C (PKC). Akt and ERK were found to be activated by fMLP.;In conclusion, resveratrol was found to be a potent inhibitor of ROS production, particularly if a peroxidase-dependent measuring principle was used. Resveratrol can be oxidised by peroxidases, which inhibit the oxidation of the redox probe. Use of a detection method that did not require peroxidase revealed that resveratrol was still a potent inhibitor of fMLP-induced ROS. Moreover, this inhibitory dose of resveratrol correlated with its ability to inhibit the PI3K-Akt pathway, one of the major regulatory pathways of fMLP-induced ROS production. Modulation of these cell signalling intermediates by resveratrol might represent an important anti-inflammatory pathway and further add to its potential cardioprotective properties.
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Wright, Denis Matthew John, and mikewood@deakin edu au. "Potential antiarrhythmic and cardioprotective agents based on adenosine." Deakin University. School of Biological and Chemical Sciences, 1998. http://tux.lib.deakin.edu.au./adt-VDU/public/adt-VDU20050915.160941.
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N-Ethylcarboxamidoadenosine (12) was synthesised from adenosine (1) and the 6-chloro-2,3-O-isopropylidene-AT-ethylcarboxamidoadenosine (25) was synthesised from inosine (19).
Employing molecular modelling techniques and the results from previous structure activity relationships it was possible to design and synthesise a N6-substituted N-ethylcarboxamidoadenosines which possessed an oxygen in the N6-substituent either in the form of an epoxide (which was obtained by cpoxidising an alkene with m-CPBA or dimethyldioxirane) or in the form of a cyclic ether as was the case for N6-((tetrahydro-2H--pyran--2-yl)methyl-N-ethylcarboxamidoadenosine (78). These compounds were tested for their biological activity at the A1 adenosine receptor by their ability to inhibit cAMP accumulation in DDT, MF2 cells. The EC50 values obtained indicated that the N6-(norborn-5-en-2-yl)-N-ethylcarboxamidoadenosines were the most potent. Of theseN6-(S-endo-norbrn-5-en-2-yI)-N-ethylcarboxaniidoadenosine (56) was the most potent (0.2 nM). N6-(exo-norborn-5-en-2-yl)-2-iodo-N-ethylcarboxamidoadenosine (79) was synthesised from guanosine (22) and was also evaluated for its potency at the A, receptor (24.8 ± 1.5 nM). At present 79 is being evaluated for its selectivity for the A1 receptor compared to the other three receptor subtypes (A2a, A2b, A3). A series of N6-(benzyl)-N-ethylcarboxamidoadenosines were synthesised with substitutions at the 4-position of the phenyl ring. Another series of compounds were
synthesised which replaced the methylene spacer between the N6H and the N6-aromatic
or lipophilic substituent The replacement groups -were carbonyl and trans-2-
cyclopropyl moieties. The N6-acyl compounds were obtained by reacting 2,3-O-
di(tert-butyldimethylsilyl)-AT-ethylcarboxamidoadenosinc (59) with the appropriate acid chloride and then deprotecting with lelrabutylammonium fluoride in
tetrahydrofuran. The compound N6-(4-(1,2-dihydroxy)ethyl)benzyl-N-
ethylcarboxamidoadenosine (125) was synthesised by the reaction of 4-(1,2-0-
isopropylidene-ethyl)benzyl aminc (123) with 6-chloro-2,3-0-isopropylidene-N-
ethylcarboxamidoadenosine (25). Compound 123 was synthesised from an
epoxidation of vinylbenzyl phthalimide (118) followed by an acidic ring opening to
yield the diol which was isopropylidenated to yield 4-(l,2-O-isopropylidene-
elhyl)benzyl phlhalimide (122), It was hoped that the presence of the diol
functionality in 125 would increase water solubility whilst maintaining potency at the
A3 receptor.
8
Sopizhenko, Nadia. "Properties of cardioprotective preparations and their antistress effect." Thesis, Київський національний університет технологій та дизайну, 2019. https://er.knutd.edu.ua/handle/123456789/13167.
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Barbalace, Maria Cristina <1988>. "17β-estradiol modulates cardioprotective effects of nutraceutical compounds." Doctoral thesis, Alma Mater Studiorum - Università di Bologna, 2018. http://amsdottorato.unibo.it/8526/1/Barbalace_Maria_Cristina_tesi.pdf.
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Cardiovascular disease rarely manifests in pre-menopausal women meanwhile, the incidence of these pathologies dramatically increases after the menopause suggesting the possibility that sex hormones could have a key role. 17β-estradiol is the main female circulating hormone in the premenopausal period and showed protective effects on the cardiovascular system. Moreover, recent evidences underlie the importance to take into account the gender in clinical studies as it can influence the response to cardiovascular medications. Therefore, we hypothesize that sex hormones can also influence the cardioprotective effects of nutraceutical compounds, such as sulforaphane, isothiocyanate present in Brassica vegetables. This study was designed to investigate the protective effects of sulforaphane in presence of 17β-estradiol against H2O2-induced oxidative damage in cardiomyocytes. 17β-estradiol enhanced sulforaphane cardioprotection against H2O2-induced cell death with respect to 17β-estradiol or sulforaphane alone, as measured by 3-(4,5-dimethylthiazol-2-yl)-2,5diphenyl-tetrazolium bromide and lactate dehydrogenase assays. Moreover, 17β-estradiol boosted sulforaphane antioxidant activity, reducing intracellular reactive oxygen species and 8-hydroxy-2′-deoxyguanosine levels and increasing the expression of phase II enzymes. The observed effects seem to be not mediated by estrogen receptor α and β, as we used specific antagonists. Otherwise, ERK1/2 and Akt signaling pathways seem to be involved, as the treatment with specific inhibitors reduced the protective effect of sulforaphane/17β-estradiol co-treatment. Furthermore, estrogen receptor β and G protein-coupled receptor 30 seem to contribute to Akt activation, as using receptor specific agonists sulforaphane-induced Akt phosphorylation was enhanced. The activation of Akt kinase is also involved in the activation of Nrf2 transcription factor elicited by sulforaphane/17β-estradiol co-treatment, as treated cells with Akt-inhibitor, the co-treatment-induced Nrf2 activation was prevented. Our results demonstrated, for the first time, that estrogen could enhance sulforaphane protective effects, suggesting that nutraceutical efficacy might be modulated by sex hormones.
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Maarman, Gerald Jerome. "Melatonin as a novel cardioprotective therapy in pulmonary hypertension." Doctoral thesis, University of Cape Town, 2014. http://hdl.handle.net/11427/12872.
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Includes bibliographical references.Pulmonary hypertension (PH) is characterized by elevated pulmonary arterial pressure which leads to right ventricular hypertrophy and failure. The mechanism involved in the pathophysiology of the disease remains unclear but it is suggested that oxidative stress may trigger cardiovascular dysfunction associated with the disease. To date, there is no efficient therapy against PH and novel therapies are urgently needed. Melatonin is a powerful antioxidant that can confer benefit against ischemia-reperfusion injury and hypertension. We therefore hypothesised that melatonin may confer cardiovascular benefits against PH. Methods: Oxidative stress (plasma lipid peroxidation, antioxidant capacity and antioxidant enzyme activity) was assessed in healthy (n=10), in patients with PH (n=10), in Long Evans rats (n≥6) or in a rat model of PH induced 28 days after the injection of monocrotaline (MCT, 80mg/kg, subcutaneous) (n≥6). Melatonin (75ng/L, nutritional concentration), 4mg/kg or 6mg/kg (therapeutic dose) was given daily in the drinking water of rats, with the treatment started 5 days before the injection of MCT, on the day of the injection or 14 days after the injection of MCT. The development of PH was measured by assessing right ventricular hypertrophy, cardiac fibrosis, oxidative stress and cardiac function (via echocardiography and the isolated heart Langendorff perfusion model). Results: Plasma oxidative stress was increased in both patients and rats with PH compared with their respective controls. A chronic treatment with melatonin (75ng/L, 4mg/kg or 6mg/kg) starting on the day of the injection with MCT in rats with PH reduced right ventricular hypertrophy, cardiac dysfunction and plasma oxidative stress compared with control rats. Furthermore, the beneficial effect of melatonin (6mg/kg) could be observed when given as a preventive (5 days prior to the injection of MCT) or as a curative therapy (14 days after the injection of MCT). Conclusions: Our data demonstrate that chronic treatment of melatonin confers cardioprotection in a rat model of PH. As melatonin is inexpensive, safe (no reported side effects) and already available over the counter in many countries, we propose that melatonin should be considered as a novel preventive/curative therapy to limit cardiac dysfunction in patients with PH.
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Lamont, Kim. "Delineation of the Cardioprotective Agents found in red wine." Master's thesis, University of Cape Town, 2009. http://hdl.handle.net/11427/3415.
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Secondary leach concentrate (SLC) is an important bleed stream for minor elements from Anglo Platinum's Base Metal Refinery (BMR) which produces copper nickel and cobalt sulphate. It contains mainly sulphur, iron jarosites, unleached base metals and platinum group metals (PGMs), which makes the treatment of SLC necessary. The SLC is currently toll-refined at Umicore's Hoboken smelter and refinery to recover revenue from entrapped valuable metals. This method of treatment results in excessively high costs due to high transport and toll refining expenses as well as penalties. Thus, an in-house method of treatment by Anglo Platinum itself would prove beneficial in that it would eliminate these excessive costs and also provide a method of treatment in the event of residues exporting becoming banned or strongly penalised in future. Therefore, a method for treating SLC in-house is investigated. The first stage of the proposed treatment method involves a pyrometallurgical process where the removal of amphoterics by oxidative fuming, followed by reduction to recover base metals from the slag takes place. The PGMs are reported mainly to the metal alloy phase along with the base metals during this process. The project discussed in this report deals with the treatment of this furnace alloy which is referred to as Cu alloy. The Cu alloy is used to produce anodes to be applied to an electrorefining application for the recovery of Cu as a Cu cathode and PGMs in the form of anode slimes. Spent electrolyte from the BMR copper electrowinning section adjusted to specific pH and Cu concentration is used as electrolyte to which dissolvable metals (such as Ni and Fe) are recovered. The purpose of the process is to recover PGMs to anode slimes with a composition suitable to be blended with the final concentrate that is sent to the Precious Metals Refinery (PMR). The performance of this process on the Cu alloy provided is investigated and the anode slimes produced are characterised in order to propose further methods of purification before blending with PMR feed. The typical energy consumption, cathodic current efficiency, anodic copper dissolution rate and deportment of elements (especially PGMs) are determined. The effects of various operating parameters on the performance are also investigated in order to propose operating conditions. The operating parameters that are investigated are current density, Cu and H2SO4 concentrations in electrolyte and the use of an additive. A preliminary process design based on knowledge and experience gained during the literature review and test work is given. -PAGE 3 OF 181 The major technical factors in electrorefining are the cathode purity, the production rate and the specific energy consumption. These factors are influenced primarily by anode quality, electrolyte conditions and cathode current density. Design considerations and typical design parameters for other industrial Cu electrorefining applications are studied as well as possible further treatment of anode slimes for the concentration of PGMs. A total of eleven experiments were performed with a variety combinations of Cu concentration (30, 40 and 50 g/l), H2SO4 concentration (110, 130, 160 and 190 g/l) and current density (100, 125, 150, 250, 300 A/m2). In each experiment only one parameter was changed while all others were kept constant at the base-case setting of 40 g/l Cu, 160 g/l H2SO4, and 125 A/m2. The testwork showed that electrolytic refining of the Cu alloy, produced by a two stage pyrometallurgical treatment of current SLC, produces a highly concentrated PGM residue at an overall SLC mass reduction of 99.3%, with excellent PGM recovery to the anode slimes material. The different operating parameters that were tested successfully, all showed very good repeatability and greater than 99% PGM recovery from the Cu alloy, which would result in an overall recovery of 98% from SLC. Very little or none of the base metals that were supplied by the anode or the electrolyte feed reported to the anode slimes. The typical operating conditions (cell potential, current efficiency, anodic Cu dissolution and element deportment) that were observed correlated well with literature and the theoretically calculated values. The characteristics of the anode slimes produced stayed relatively similar throughout the different operating parameters and strong confidence can be placed in the production thereof and the recovery of the PGMs. The characteristics of the spent electrolyte and the Cu cathodes were also found to be suitable for integration in the BMR circuit. The anode slimes composition was 20 to 30% PGMs, 20 to 30% base metals, 15 to 20% Ag, As, Te, Se, Pb and 2 to 5% Al, Si, Sb, Bi, Zn and Sn. The blending of these slimes with typical PMR feed will result in a new PMR feed where the Pt grade of the feed to PMR is reduced by 4 to 5.5%, the Cu grade increased by 2 to 4% and the Ni content reduced by +-4%. Other concerns are the increase of As, Te, and Pb by between 0.5 and 1%. -PAGE 4 OF 181 The PGM-rich (<60%) phase in the anode slimes is a mostly amorphous matrix phase containing mostly palladium and other PGMs, arsenic and tellurium [Pd73As6Te21] with small amounts of Cu. Anode slimes produced from electrorefining can either be subjected to an additional process step to remove Ag, Pb and base metals before it is blended with the final concentrate (FICO) as feed for PMR, or it can be sent to the metallics section in PMR which includes a roast and a leach stage. The treatment of the anode slimes depends on the nature of the slimes. A preliminary process design was performed with proposed design parameters of electrolyte concentrations of 40 g/l Cu and 160 g/l H2SO4 at 65 deg C and a current density of 200 A/m2. The process consists out of seven cells in series with 55 anode cathode pairs in parallel per cell. The process has a maximum capacity of 127 t/m of anode material which allows 56 days of downtime per year if the current SLC produced (6600 t/a) is treated. The maximum capacity for Cu production is 1349 t/a and anode slimes 50.3 t/m. The power consumption per kg of anode dissolved will be 0.175 kWh/kg.
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Abdul-Ghani, Safa. "Mechanisms underlying the cardioprotective effect of remote ischaemic preconditioning." Thesis, University of Bristol, 2015. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.687185.
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Coronary heart disease (CHD) is one of the leading causes of morbidity and mortality in the world. Intervention to treat the diseased heart includes cardiac surgery using cardiopulmonary bypass and cardioplegic ischaemic arrest. Blood supply restoration to the heali, at the end of ischaemic arrest, results in reperfusion injury and cardiac death by necrosis and apoptosis. Research in recent years has shown that the heart has endogenous mechanisms that can be used for protection (e.g. conditioning). Remote Ischaemic Preconditioning (RIPC) is a phenomenon where preconditioning of organs distant to the heart can protect the myocardium against index ischaemia and reperfusion (I/R) injury. However, translating this intervention to clinical practice has been delayed due to lack of understanding of the nature of the triggers and the mediators and more importantly the lack of understanding of cellular changes in myocardium prior to I1R. The overall aim of this study was to establish a mouse model of RIPC and to investigate the nature of the released trigger and the cellular changes in the myocardium associated with RIPC. In this work we characterized a mouse model of RIPC and investigated the cardioprotective effect of RIPC following I1R. In vivo and in vitro techniques (e.g. Tandem Mass Tags & mass spectrometric-based quantitative proteomics, western blotting, ELISA immunoassay, electrocardiography, Laser Doppler Flowmetry, High Performance Liquid Chromatography and Langendorffheart perfusion) were used to address the aim of this thesis. Our model of 4 cycles of hindlimb RIPC is cardioprotective as shown by reducing infarct size, creatine kinase release and improving functional recovery after (I/R) of Langendorff heati. RIPC was associated with an increase in heart rate as measured in isolated perfused heali. This effect was further confirmed in vivo and the ECG data was used to carry out heart rate variability analysis. This suggested that RIPC induces a sympathetic drive which can be α- or β-stimulation. Evidence for increased p-stimulation was shown by increased phosphorylation of proteins known to be activated by PKA (ryanodine receptor and myozenin). This stimulation appears to trigger cardiac ischaemic stress (elevated AMP/ A TP & ADP/ ATP ratios). RIPC was also associated with reduced microcirculatory blood flow (MBF) in the second uncuffed hindlimb which could be due to α-sympathetic stimulation causing vasoconstriction. RIPC induced phosphorylation of proteins linked to key signalling pathways and localized to the Z-disk of the sarcomere could be responsible for cardioprotection. Additionally, RIPC was found to cause significant accumulation of adenosine (associated with ischaemic stress) which is known to be cardioprotective. Interestingly, RIPC did not activate PKCα. or the RISK pathway proteins in tissue harvested immediately after the induction of RIPC. In conclusion, RIPC is associated with increased sympathetic drive which activates key Z-disk phosphoproteins, changes in MBF, ischaemically stress the myocardium and increases adenosine myocardial content. These changes confer protection against I/R.
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FABBRI, Martina. "Design and synthesis of potential cardioprotective agents targeting mitochondria." Doctoral thesis, Università degli studi di Ferrara, 2023. https://hdl.handle.net/11392/2504897.
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Despite recent advances and success in interventional coronary reperfusion strategies, acute myocardial infarction (MI) is recognized as one of the most frequent forms of ischemic heart disease and one of the leading causes of death in Western countries. The so-called reperfusion injury (RI) contributes for up to the 50% of the final infarct size, thus restricting the efficacy of primary percutaneous coronary intervention. Rising data indicate that the onset of RI involves several molecular and cellular factors that culminate in the final opening of a large pore in the mitochondrial membrane, namely the mitochondrial permeability transition pore (mPTP). mPTP is recognized as one of the main biochemical processes responsible for RI and for cardiomyocyte death, as well as a major therapeutic target for cardioprotection. mPTP is defined as a multiprotein platform including pore-forming elements and modulators that contribute to its open/closed conformational state. Several mPTP inhibitors have been identified, among which Cyclosporin A (CsA) and TRO-40303 have reached clinical studies. However, inconsistent results have been achieved as far as their cardioprotective action. The incomplete knowledge of the bio architecture of mPTP is the main obstacle in drug discovery programs. Recent data point to a role for ATP synthase in mPTP formation. According to this model, peculiar changes can convert the energy-supplying ATP synthase machine into an energy-dissipating supramolecular entity, mPTP. Independent studies provided that the c-subunit of F1FO-ATP synthase plays a pivotal role in mPTP formation. The main triggers of mPTP opening are the increase of intra-mitochondrial calcium concentration and of reactive oxygen species (ROS) by-products. Additionally, ROS may lead per-se to target-organ damage, dysfunction, hypertrophy and inflammation. Considering the unmet need with respect to RI therapy and novel cardioprotective strategies, this doctoral thesis has focused on the following objectives: 1) Discovery of mPTP inhibitors targeting the c-subunit of ATP synthase as cardioprotective agents: the medchem activity resulted in the identification of three new series of spiro compounds. Firstly, it has been examined the isatin ring, a scaffold that has attracted strong interest in medicinal chemistry. More complex spiro templates have been then explored, with the perspective of expanding the range of chemotypes in this research area. Finally, a solid-phase strategy has been applied in order to synthesize a library of spiro-piperidine derivatives. The potency of all the synthesized compounds was assessed through the in vitro cobalt-calcein assay. 2) Design and synthesis of molecular tools to be employed for the identification of the binding site of our molecules at the target protein and the detection of possible off-targets: in order to guide the research towards a more rational structure-based drug design approach, two series of photo-affinity labeling probes (PAPs), containing a photoreactive unit and an alkyne handle, have been developed. Among the investigated PAPs, two suitable tools have been discovered, which may be extremely useful to progress in this medchem area. 3) Design of novel mitochondria-targeted cardioprotective agents potentially able to scavenge redox-active transition metal ions: since ROS are strongly implicated in IRI and iron ions in the mitochondrial environment are known to exert a prooxidant action, derivatives composed of an iron chelator (DFO) linked to a mitochondria-targeted drug delivery system (peptide SS31) have been designed, synthesized and characterized. The two classes of compounds resulting from the final doctoral thesis, spirocyclic mPTP inhibitors and antioxidant agents, could exert a synergistic cardioprotective action upon co-administration that will be investigated in future studies.Nonostante i recenti progressi nelle strategie interventistiche di riperfusione coronarica, l'infarto miocardico acuto (MI) è una delle forme più frequenti di cardiopatia ischemica e delle principali cause di morte nei Paesi occidentali. Il cosiddetto danno da riperfusione (RI) contribuisce fino al 50% della dimensione finale dell'infarto, limitando l'efficacia dell'intervento coronarico percutaneo. Dati in crescita indicano che l'insorgenza del RI coinvolge vari fattori molecolari e cellulari i quali culminano nella finale apertura di un poro nella membrana mitocondriale, il poro di transizione della permeabilità mitocondriale (mPTP). mPTP è noto come uno dei principali processi responsabili del RI e della morte dei cardiomiociti, nonché un bersaglio terapeutico per la cardioprotezione. mPTP è definito come una piattaforma multiproteica costituita da elementi strutturali e modulatori che contribuiscono al suo stato conformazionale aperto/chiuso. Sono stati identificati diversi inibitori di mPTP, tra cui Ciclosporina A (CsA) e TRO-40303 che hanno raggiunto gli studi clinici, con risultati incoerenti per quanto riguarda la loro azione cardioprotettiva. L’incompleta conoscenza della struttura di mPTP è il principale ostacolo nella scoperta di nuovi farmaci. Dati recenti mostrano il reclutamento della ATP sintasi nella formazione di mPTP. Secondo tale modello, specifici cambiamenti possono convertire l’enzima ATP sintasi che fornisce energia in un'entità supramolecolare che dissipa energia, mPTP. Varie ricerche hanno provato che la subunità c della F1FO-ATP sintasi svolge un ruolo centrale nella formazione di mPTP. I principali “triggers” dell'apertura di mPTP sono l'aumento della concentrazione di calcio intra-mitocondriale e delle specie reattive dell'ossigeno (ROS). Inoltre, i ROS possono di per sé portare a danni agli organi, disfunzioni, ipertrofia e infiammazione. Considerando il bisogno insoddisfatto di terapie del RI e di nuove strategie cardioprotettive, la tesi di dottorato si è focalizzata sui seguenti obiettivi: 1) Scoperta di nuovi inibitori di mPTP mirati alla subunità c dell'ATP sintasi come agenti cardioprotettivi: l'attività svolta ha portato all'identificazione di tre serie di spiro-composti. In primo luogo, è stato esaminato il nucleo isatinico, uno scaffold che ha suscitato interesse nella chimica farmaceutica. Sono stati poi esplorati modelli più complessi, con la prospettiva di ampliare la gamma di chemotipi in questo settore di ricerca. Infine, è stata applicata una strategia di sintesi in fase solida per ottenere una libreria di derivati spiro-piperidinici. La potenza di tutti i composti è stata valutata in vitro mediante il saggio cobalto-calceina. 2) Progettazione e sintesi di “tools” per l'identificazione del sito di legame delle nostre molecole alla proteina bersaglio e l'individuazione di eventuali off-targets: al fine di orientare la ricerca verso un approccio più razionale di progettazione di farmaci, sono state sviluppate due serie di sonde di foto-affinità (PAPs), contenenti un'unità fotoreattiva e un gruppo alchino. Tra le PAPs studiate, sono stati identificati due promettenti candidati, potenzialmente utili per progredire in questo settore di ricerca. 3) Progettazione di nuovi agenti cardioprotettivi mirati ai mitocondri, come potenziali “scavenge” di ioni di metalli di transizione redox-attivi: poiché i ROS sono implicati nell'IRI e gli ioni ferro, nell'ambiente mitocondriale, sono noti per esercitare un'azione pro-ossidante, sono stati progettati, sintetizzati e caratterizzati derivati costituiti da un chelante del ferro (DFO) legato a un “drug delivery” mirato ai mitocondri (peptide SS31). Le due classi di composti risultanti dalla tesi finale di dottorato, inibitori spiro-ciclici di mPTP e agenti antiossidanti, potrebbero esercitare un'azione cardioprotettiva sinergica, in caso di co-somministrazione, che sarà indagata in studi futuri.
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Mariappan, G. "Cardioprotective properties of pyrazotone derivatives in myocardial ischemic reperfusion injury." Thesis, University of North Bengal, 2011. http://hdl.handle.net/123456789/1501.
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Stote, Kim Storti Kurlandsky Sara. "Cardioprotective effects of chocolate and almond consumption in healthy women." Related electronic resource: Current Research at SU : database of SU dissertations, recent titles available full text, 2004. http://wwwlib.umi.com/cr/syr/main.
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Waard, Monique Chantal de. "Cardioprotective effects of exercise training the importance of nitric oxide /." [S.l.] : Rotterdam : [The Author] ; Erasmus University [Host], 2008. http://hdl.handle.net/1765/13206.
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Ebrahim, Zaileen. "Cardioprotective actions of bradykinin in the normal and hypertrophied myocardium." Thesis, University College London (University of London), 2001. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.249678.
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Basudhar, Debashree. "NITROGEN OXIDE RELEASING PRODRUGS AS ANTIINFLAMMATORY, ANTICANCER AND CARDIOPROTECTIVE AGENTS." Diss., The University of Arizona, 2011. http://hdl.handle.net/10150/145745.
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This dissertation focuses on chemical and biological evaluation of diazeniumdiolate based nitrogen oxide releasing prodrugs. Three projects are described. i. Synthesis and biological evaluation of a series of new nitroxyl (HNO) releasing non-steroidal antiinflammatory drugs (NSAIDs) and comparison to related nitric oxide (NO) releasing NSAIDs A series of HNO releasing isopropylamine-based diazeniumdiolate adducts of NSAIDs and the NO releasing diethylamine diazeniumdiolate counterpart were synthesized. The aspirin derivatives were evaluated for antiinflammatory, cardioprotective and anticancer effects. Both prodrugs demonstrated similar antiinflammatory properties to aspirin but significantly lower gastrointestinal ulceration, which is a common side effect of aspirin. The HNO adduct also improved cardiac contractility. The chemotherapeutic potential of the prodrugs was assessed in vitro and in vivo. Both the prodrugs inhibited growth of cultured carcinoma cells without inducing cytotoxicity towards non-tumorogenic cell lines. The higher cytotoxicity of the HNO adduct was in part due to increased production of reactive nitrogen and oxygen species leading to oxidative damage to DNA, inhibition of glyceraldehydes-3-phosphate dehydrogenase and upregulation of signaling pathways leading to caspase-3 mediated induction of apoptosis. The NO adduct is a promising candidate for reduction of metastasis by increasing E-cadherin levels, which influences cellular adhesion. Both derivatives showed significantly reduced angiogenesis in cultured cells and tumor volume in nude mice. ii. Synthesis and characterization of primary amine based cyclic amine diazeniumdiolates and comparison to their acetoxy methyl ester derivatives. A series of HNO releasing cyclic amine diazeniumdiolates were synthesized to expand upon the few examples of primary amine diazeniumdiolates. An ester derivative of cyclopentylamine NONOate was also synthesized, to increase decomposition half-life and to improve HNO production and better cellular uptake. This modification increased its cytotoxicity compared to ionic NONOates. iii. Evaluation of mechanism of action of JS-K. JS-K (O²-(2,4-dinitrophenyl)-1-[(4-ethoxycarbonyl)-piperazin-1-yl]-diazeniumdiolate) has previously been found to be highly cytotoxic in many cancer cell lines compared to ionic diazeniumdiolates. Thus, the role of NO in cytotoxicity of JS-K was explored. A low intracellular NO flux in combination with a lack of any effect on cyclic guanosine monophosphate (cGMP) dependent pathway suggests that NO is not directly responsible for the cytotoxicity of JS-K.
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Cairncross, Samantha Inga. "The evaluation of the cardioprotective effects of Olea containing liposomes." University of the Western Cape, 2017. http://hdl.handle.net/11394/6055.
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Magister Scientiae - MSc (Medical BioSciences)High levels of free oxygen radicals, induced by many biological or environmental factors, result in damage and dysfunction of the mitochondria which causes cardiovascular and other diseases. Cardiotherapies employing antioxidants has been suggested to be a useful approach to scavenge excess reactive oxygen species (ROS). Many phytomedicines have antioxidant properties. The outcome of many clinical trials in which phytomedicines were used is however often disappointing.
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Hepburn, Claire Y. "Studies investigating the mechanisms of the cardioprotective effects of cannabidiol." Thesis, Robert Gordon University, 2014. http://hdl.handle.net/10059/1002.
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The phytocannabinoid cannabidiol (CBD) has a complex pharmacology which is thought to include, but is not limited to, an ability to act as an inverse agonist at the CB1 and CB2 receptors and an antagonist of GPR55. Moreover, is has been shown to reduce infarct size and ameliorate reductions in left ventricular function in vivo. These improvements in the pathogenesis of experimental MI are accompanied by a reduction in inflammatory cell migration to the area at risk. More recently it has been shown that CBD is anti-arrhythmic in acute experimental MI. Thus, it was suggested that the cardioprotective effects of CBD might be due to an anti-inflammatory action. In addition, GPR55 receptor activation is acknowledged to mediate mobilisation of intracellular Ca2+ (Ca2+i) which could potentially be pro-arrhythmic and so CBD, as an antagonist may confer cardioprotection via GPR55. However, the receptors and/or mechanisms responsible for mediating the cardioprotective effects of CBD are get to be determined. The present studies were therefore performed to; (1) better understand the pharmacology of CBD by assessing haemodynamic responses to CBD and other cannabinoids ligands in anaesthetised rats, (2) investigate the receptors involved in the anti-arrhythmic effect of CBD in a rat model of coronary artery occlusion (CAO), and (3) investigate if CBD can alter [Ca2+]i in isolated rat cardiomyocytes. The characterisation of the pharmacology of CBD in vivo showed that; firstly, CB1 receptor activation causes a hypotensive response which can be dose-dependently inhibited by AM251; secondly, both CBD and AM251 alone (a CB1 receptor antagonist and GPR55 agonist) can induce vasodepressor responses and finally, CBD can potentiate the AM251-mediated hypotension when co-administered, suggesting possible cross-talk between the CB1 and GPR55. Results from CAO studies showed that CBD and AM251 each have the capacity to reduce arrhythmias. Moreover, when CBD and AM251 were co-administered the anti-arrhythmic capacity of either alone was potentiated. However, the degree of potentiation was dependent on the order of administration, suggesting that more than one receptor is involved in the summative anti-arrhythmic effects. The investigation of cardiomyocyte [Ca2+]i suggested that AM251 can modulate [Ca2+]i at the level of the cardiomyocyte, while CBD cannot. These data give novel insight into the anti-arrhythmic effects of CBD and, moreover, for the first time demonstrate that AM251 is anti-arrhythmic. In addition, these data suggest a role for GPR55 in increasing [Ca2+]i via AM251.
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Griffin, Michael O. "Mechanisms underlying the cardioprotective effects of tetracyclines in myocardial ischemic injury." Diss., Connect to a 24 p. preview or request complete full text in PDF format. Access restricted to UC campuses, 2007. http://wwwlib.umi.com/cr/ucsd/fullcit?p3283466.
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Thesis (Ph. D.)--University of California, San Diego, 2007.Title from first page of PDF file (viewed June 2, 2008). Available via ProQuest Digital Dissertations. Vita. Includes bibliographical references (p. 145-165).
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Eccleston, Clair. "Physiological and molecular mechanisms underlying the cardioprotective effects of dietary antioxidants." Thesis, University of Reading, 2003. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.409047.
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Pickard, Olubukunola. "Synthesis and cardioprotective activities of green tea polyphenols and their analogues." Thesis, University of Southampton, 2014. https://eprints.soton.ac.uk/362977/.
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Cardiovascular disease is a major killer worldwide and it is becoming clear the significance of our diet in curbing the disease. Green tea is one of the most widely consumed beverages in the world and has recently attracted significant attention in the scientific community for its health benefits. Its consumption has been associated with lower incidences of coronary artery diseases in the Japanese population. This is mainly attributed to its polyphenolic constituents that include epicatechin, epicatechin gallate, epigallocatechin and epigallocatechin gallate. The aim of this research was to synthesise the four major polyphenols present in green as well as analogues. These compounds would then be tested on H9C2 cardiac myoblast cells and neonatal rat cardiomyocytes in order to further understand the structure-activity relationship as well as potentially improve the cardioprotective function of these polyphenols following oxidative stress and ischaemia/reperfusion injury focusing on the expression of STAT-1 and ERK-1/2 proteins. In H9C2 cardiac myoblast cells following the induction of oxidative stress using H2O2, EGCG, EGC and to a minor extent ECG inhibited STAT-1 activation but not ERK- 1/2 phosphorylation suggesting that although the ERK-1/2 pathway gets activated, its downstream activation of STAT-1 is inhibited by the above polyphenols. EC, on the other hand, inhibited ERK-1/2 activation which in turn cannot activate STAT-1. Quantitative assessment of viable cells showed that pretreatment with EGCG resulted in the lowest amount of non-viable cells reducing cell death by 30%. With neonatal rat cardiomyocytes following ischaemia/reperfusion injury, pretreatment with EGCG reduced the amount of non viable cells by 5% but pretreatment with acetylated EGCG at half the concentration of EGCG reduced non-viable cells by 8%. Structure-activity relationships of the green tea polyphenol analogues identified some key aspects in the structures of the polyphenols important in their cardioprotective function. Results indicated that ABD ring system is required for cardioprotective function but the presence of a third OH group in the ring may not be necessary. Substitution of ring C with benzoic and naphthoic rings improved the potency by more than 13-fold compared to EGCG with EC50 values of 1.60 and 0.77 μM respectively. Further research into these analogues could realise their potential and contribute to the understanding of the cardioprotective activities of green tea. A review on the previous synthesis approaches, isolation and biosynthesis of the green tea polyphenols is presented in Chapter 1 and also the different signalling pathways of interest in this work. An evaluation of the biological activities of the four major polyphenols is provided in Chapter 3. Experimental procedure and characterisation data are in Chapter 5.
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Dlamini, Lindizwe. "Exploring the cardioprotective effect of synthetic wine in Long Evans rats." Master's thesis, University of Cape Town, 2015. http://hdl.handle.net/11427/15763.
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[No copyright notice] Background: Moderate and chronic consumption of red wine protects against cardiovascular disease. Wine is a complex matrix containing multiple molecules whose concentrations can vary from one bottle to another. Therefore, the delineation of the putative cardioprotective components in wine such as alcohol, resveratrol and melatonin is very challenging when using commercially available red wine. Aim: We aimed to use synthetic wine, whose composition is well characterized, to explore whether the presence of alcohol, resveratrol and melatonin (as found in commercial wines) contributes to the cardioprotective effect of chronic and moderate consumption of red wine (equivalent to 2 glasses of wine/day) in an animal model. Additionally, we hypothesized that synthetic wine enriched with resveratrol and melatonin confers cardioprotection via improvement of overall antioxidant profile.
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Reidlinger, Dianne Patricia. "Evidence, benefits and barriers to achieving an integrated cardioprotective dietary pattern." Thesis, King's College London (University of London), 2015. http://kclpure.kcl.ac.uk/portal/en/theses/evidence-benefits-and-barriers-to-achieving-an-integrated-cardioprotective-dietary-pattern(b9ac6fb9-ded1-4ed9-a2c0-b77ca143a419).html.
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This thesis investigated the hypothesis that modifying the overall dietary pattern to conform with UK dietary guidelines would lead to significant reductions in cardiovascular risk factors when compared to a conventional UK diet. Two additional studies were undertaken: a qualitative study exploring factors influencing compliance to the dietary intervention and an investigation into whether a cardioprotective dietary pattern is more expensive than a conventional UK dietary pattern. An integrated dietary intervention consistent with UK dietary guidelines (5 portions of fruit and vegetables per day, increased consumption of whole grain cereals and oily fish; moderate total fat; reduced saturated fat, added sugars and salt intake) was developed. Changes in daytime systolic blood pressure, ratio of total cholesterol to HDL cholesterol, and endothelial function were compared after 12 weeks in healthy adults aged 40 to 70 years following either the cardioprotective diet (n=80) or a representative UK diet (n=82). There was a significant reduction in daytime SBP of 4.2 mmHg and a 4.2% reduction in TC:HDL-C compared to the control diet, however endothelial function did not differ between groups. Participants randomised to the cardioprotective diet (n=8) were interviewed in a qualitative study. Motivators identified were sociocultural; many specific to the study context. Elements were identified that could be implemented outside of a scientific study environment. Participants adopted a number of strategies in response to social and environmental barriers, some of which would be hard to maintain in the longer term. A retrospective analysis of food records completed by a subset of participants (n=40) found there was no difference in the cost of the two diets at endpoint, nor was there a difference in dietary costs compared to baseline. The work described suggests that the adoption of a dietary pattern consistent with UK dietary guidelines does improve cardiovascular risk. Cost may not be a barrier to adopting a cardioprotective dietary pattern in individuals who are not specifically of lower socioeconomic status. These findings and factors affecting compliance to the intervention are discussed in relation to the translation beyond the trial setting to inform public health initiatives for cardiovascular disease prevention.
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Pushparaj, Charumathi. "Pharmacological blockade of voltage-gated calcium channels as a potential cardioprotective strategy." Doctoral thesis, Universitat de Lleida, 2014. http://hdl.handle.net/10803/285047.
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Voltage-gated Ca2+ channels (VGCCs) are essential for initiating and regulating cardiac function. During the cardiac action potential, Ca2+ influx through L-type channels triggers the sarcoplasmic reticulum Ca2+ release that enables the EC coupling. Ca2+ can also enter cardiac myocytes through low-voltage-activated T-type channels, which are expressed throughout cardiac development until the end of the neonatal period, and can contribute to pacemaker activity as well as EC coupling to some extent. Importantly, T-type channels are re-expressed in ventricular myocytes under diverse pathological conditions such as ischemia or hypertrophy, suggesting that they play a role in cardiac disease. In a first part of this study, we examined the effects of VGCC blockers on the homeostasis and viability of primary cultures of cardiac myocytes (CMs), because of the importance of apoptosis and necrosis in cardiac disease. In a second part, we analyzed the cell mechanisms unleashed by hypoxic and hypertrophic stimuli, the involvement of VGCCs and the putative cytoprotective effects of VGCC blockade. Our results show that L-type and T-type channel blockers induce a low-level and transient ER stress, albeit with a distinct conveyance into cell macroautophagy and viability: whereas L-type channel blockers trigger a macroautophagic process in CMs, ultimately promoting apoptosis, T-type channel blockers exerts the opposite effect, by decreasing the autophagic flux and not affecting cell death. Furthermore, the blockade of T-type channels reduces Beclin-1-dependent autophagy and protects CMs subject to hypoxia-reoxygenation (as an in vitro paradigm for ischemia-reperfusion). We thus identify L-type and T-type channels as new targets for macroautophagy regulation of CMs, and provide new clues to the beneficial actions reported in clinical trials for T-type channel blockers, particularly against pathophysiological conditions involving a maladaptive autophagy.Els canals de calci dependents de voltatge (CCDV) són essencials per a iniciar i regular la funció cardíaca.Durant el potencial d'acció cardíac, l'influx de Ca2+ a través dels canals de tipus L desencadena l'alliberament de Ca2+ del reticle sarcoplasmàtic necessària per l'acoblament E-C. El Ca2+ també pot entrar en els miòcits a través de canals de Ca2+ de tipus T, que s'expréssen durant el desenvolupament cardíac fins el final del període neonatal, i poden contribuïr a l'activitat marcapassos així com a l'acoblament EC. De forma destacable, els canals de tipus T es re-expréssen als cardiomiòcits ventriculars en diverses condicions patològiques com la isquèmia i la hipertròfia, el què suggereix que juguen un rol relevant en l'enfermetat cardíaca. En una primera part d'aquest estudi, vàrem examinar els efectes dels bloquejants de CCDV sobre l'homeostasi i la viabilitat de cultius primaris de cardiomiòcits (CMs), degut a la importància de l'apoptosi i la necrosi en l'enfermetat cardíaca. En una segona part, vàrem analitzar els mecanismes cel·lulars desencadenats per estímuls d'hipòxia i d'hipertròfia, així com l'implicació dels CCDV i els possibles efectes citoprotectors deguts al bloqueig dels CCDV. Els resultats obtinguts mostren que els bloquejants de canals de tipus L i T indueixen un estrés de reticle de baix nivell i transitori, però que divergeixem pel què fa al seu efecte sobre la viabilitat celular: mentre que els bloquejants de canals de tipus L exacerben la macroautofàgia, provocant la mort cel·lular, els bloquejants de canals de tipus T redueixen el flux autofàgic i no afecten negativament la viabilitat dels CMs. Addicionalment, el bloqueig dels canals de tipus T redueix l' autofàgia dependent de Beclin-1 i protegeix els CMs tractats amb hipòxia-reoxigenació (un paradigma in vitro de l'isquèmia-reperfusió). En definitiva, en aquets estudi hem identificat els canals de tipus L i T com a noves dianes per la regulació de l'autofàgia en CMs, i obtingut dades novedoses sobre les accions beneficioses dels bloquejants de canals de tipus T descrites en assaigs clínics, particularment front patologies que impliquen una autofàgia maladaptativa.
Los canales de calcio voltaje-dependientes (CCDV) son esenciales para iniciar y regular la función cardíaca.Durante el potencial de acción cardíaco, el influjo de Ca2+ a través de los canales de tipo L desencadena la liberación de Ca2+ del retículo sarcoplasmático necesaria para el excitación-contracción (EC). El Ca2+ también puede entrar en los miocitos a través de canales de Ca2+ de bajo umbral o tipo T, que se expresan a lo largo del desarrollo cardíaco hasta el final del período neonatal, y pueden contribuir a la actividad marcapasos así como al acoplamiento EC. De forma destacable, los canales de tipo T se re-expresan en cardiomiocitos ventriculares bajo diversas condiciones patológicas incluyendo la isquemia y la hipertrofia, sugiriendo que juegan un rol relevane en la enfermedad cardíaca. En una primera parte de este estudio, examinamos los efectos de los bloqueantes de CCDV sobre la viabilidad y la homeostasis de cultivos primarios de cardiomiocitos (CMs), debido a la importancia de la apoptosis y la necrosis en la enfermedad cardíaca. En una segunda parte, analizamos los mecanismos celulares desencadenados por estímulos de hipoxia e hipertrofia, así como la implicación de los CCDV y los posibles efectos citoprotectores debidos al bloqueo de los CCDV. Nuestros resultados muestran que los bloqueantes de canales de tipo L y T inducen un estrés de retículo de bajo nivel y transitorio, aunque divergiendo en lo que respecta la viabilidad celular: mientras que los bloqueantes de canales de tipo L exacerban la macroautofagia, provocando la muerte celular, los bloqueantes de canales de tipo T reducen el flujo autofágico y no afectan negativamente a la viabilidad de los CMs. Adicionalmente, el bloqueo de los canales de tipo T reduce la autofagia dependiente de Beclin1 y protege a los CMs tratados con hipoxia-reoxigenación (un paradigma in vitro de la isquemia-reperfusión). Con respecto al efecto de la estimulación hipertrófica, los resultados conseguidos perfilan un escenario complejo en el que la macroautofagia constitutiva de los cardiomiocitos es inhibida, dando paso a formas alternativas de degradación proteica. En conclusión, en este estudio hemos identificado a los canales de tipo L y T como nuevas dianas para la regulación de la autofagia en CMs, y obtenido datos novedosos sobre las acciones beneficiosas de los bloqueantes de canales de tipo T descritas en esayos clínicos, particularmente frente a condiciones patofisiológicas que implican una autofagia maladaptativa.
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Hamad, Bashar M. H. "Synthesis and pharmacological evaluation of novel khellin analogues as potential cardioprotective agents." Thesis, Coventry University, 2004. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.404720.
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Rachel, Mary Fox. "An investigation into the control of mitochondrial calcium handling by cardioprotective agents." Thesis, University of Sunderland, 1992. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.315342.
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Giblett, Joel Peter. "Cardioprotective effects of Glucagon-like Peptide 1 (GLP-1) and their mechanisms." Thesis, University of Cambridge, 2017. https://www.repository.cam.ac.uk/handle/1810/263201.
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Background: Glucagon-like Peptide 1 (GLP-1) is a human incretin hormone that has been demonstrated to protect against non-lethal ischaemia reperfusion injury in the left ventricle in humans. It has been suggested from some animal research that this protection may be mediated through the pathway of ischaemic conditioning, of which the opening of the mKATP channel is a key step. Furthermore, it is uncertain whether the protection applies to the right ventricle. Finally, there is limited human evidence of a protective effect against lethal ischaemia reperfusion injury. Methods: Two studies use non-lethal ischaemia to test whether GLP-1 protection is maintained despite blockade of the mKATP channel with the sulfonylurea, glibenclamide. A demand ischaemia study uses dobutamine stress echo to compare LV function. The other uses transient coronary balloon occlusion to generate supply ischaemia during GLP-1 infusion, assessed by conductance catheter. A further transient balloon occlusion is also used to assess the effect of supply ischaemia on RV function. Finally, the GOLD PCI study assesses whether GLP-1 protects against periprocedural myocardial infarction when administered during elective PCI in a randomised, placebo controlled double blind trial. Results: Glibenclamide did not affect GLP-1 cardioprotection in either supply of demand ischaemia suggesting that GLP-1 protection is not mediated through the mKATP channel. The RV experienced stunning with RCA balloon occlusion but there was little evidence of cumulative ischaemic dysfunction with further occlusions. GOLD PCI is continuing to recruit patients. The nature of the study means results cannot be assessed until recruitment is complete. Conclusions: GLP-1 is an agent with potential for clinical use as a cardioprotective therapy. It’s mechanism of action in the heart remains uncertain.
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Garlid, Anders Olav. "Mitochondrial Reactive Oxygen Species (ROS): Which ROS is Responsible for Cardioprotective Signaling?" PDXScholar, 2014. https://pdxscholar.library.pdx.edu/open_access_etds/1641.
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Mitochondria are the major effectors of cardioprotection by procedures that open the mitochondrial ATP-sensitive potassium channel (mitoKATP), including ischemic and pharmacological preconditioning. MitoKATP opening leads to increased reactive oxygen species (ROS), which then activate a mitoKATP-associated PKCε, which phosphorylates mitoKATP and leaves it in a persistent open state (Costa, ADT and Garlid, KD. Am J Physiol 295, H874-82, 2008). Superoxide (O2•-), hydrogen peroxide (H2O2), and hydroxyl radical (HO•) have each been proposed as the signaling ROS but the identity of the ROS responsible for this feedback effect is not known. Superoxide was excluded in earlier work on the basis that it does not activate PKCε and does not induce mitoKATP opening.To further examine the identity of the signaling ROS, respiring rat heart mitochondria were preincubated with ATP and diazoxide to induce the phosphorylation-dependent open state, together with agents that may interrupt feedback activation of mitoKATP by ROS scavenging or by blocking ROS transformations. Swelling assays of the preincubated mitochondria revealed that dimethylsulfoxide (DMSO), dimethylformamide (DMF), deferoxamine, trolox, and bromoenol lactone (BEL) each blocked the ROS-dependent open state but catalase did not interfere with this step. The lack of a catalase effect and the inhibitory effects of agents acting downstream of HO• excludes H2O2 as the endogenous signaling ROS and focuses attention on HO•. In support of the hypothesis that HO• is required, we also found that HO•-scavenging by DMF blocked cardioprotection by both ischemic preconditioning and diazoxide in the Langendorff perfused rat heart. HO• itself cannot act as a signaling molecule, because its lifetime is too short and it reacts immediately with nearest neighbor phospholipids and proteins. Therefore, these findings point to a product of phospholipid peroxidation, such as hydroperoxy-fatty acids. Indeed, this hypothesis was supported by the finding that hydroperoxylinoleic acid (LAOOH) opens the ATP-inhibited mitoKATP in isolated mitochondria. This effect was blocked by the specific PKCε inhibitor peptide εV1-2, showing that LAOOH activates the mitoKATP-associated PKCε. During ischemia, catabolism of mitochondrial phospholipids is accelerated, causing accumulation of plasmalogens and free fatty acids (FA) in the heart by the action of calcium independent phospholipases A2 (iPLA2). We first assessed the role of FAs and hydroxy FAs on mitoKATP opening and cardioprotection. Swelling assays of isolated rat heart mitochondria showed that naturally formed free FAs inhibit mitoKATP opening and that they are more potent inhibitors of the pharmacological open state of mitoKATP than the phosphorylation-dependent open state. That is, sustained mitoKATP opening induced by the phosphorylation-dependent feedback loop is more resistant to FA inhibition than direct mitoKATP opening by a potassium channel opener. Moreover, rat hearts perfused with micromolar concentrations of FA were resistant to cardioprotection by diazoxide or ischemic preconditioning. Racemic bromoenol lactone (BEL), a selective inhibitor of iPLA2, confers protection to otherwise untreated Langendorff perfused hearts by preventing ischemic FA release. To bring this story full circle, BEL blocks protection afforded by preconditioning and postconditioning by preventing the iPLA2-mediated release of FAOOH generated in the conditioned heart. HO• resulting from mitoKATP opening oxidizes polyunsaturated fatty acid components of the membrane phospholipids, resulting in a peroxidized side chain. FAOOH must be released in order to act on the mitochondrial PKCε, and this is achieved by the action of iPLA2. iPLA2 is essential for most modes of cardioprotection because it catalyzes the release of FAOOH. This fully supports the hypothesis that the second messenger of cardioprotective ROS-mediated signaling is hydroperoxy fatty acid (FAOOH), a downstream oxidation product of HO•.
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Pavlovic, Marijana. "Propofol mediated cardioprotective signal transduction : ETAR dependence and caveolar effects in H9c2 cardiomyoblasts." Thesis, University of British Columbia, 2015. http://hdl.handle.net/2429/54930.
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Propofol is cardioprotective in the context of ischaemia-reperfusion. Components involved in propofol-mediated signaling involve AKT and STAT3. However, the involvement of the plasma membrane has not yet been elucidated. We hypothesized that propofol depends on two components located within the membrane — endothelin A receptor (ETAR) and caveolin.
H9c2 cardiomyoblasts were propofol-treated. To determine propofol-signaling dependence on ETAR, the selective ETAR inhibitor, PD156707 was used, and pSTAT3 Y705 protein levels were measured as a functional outcome. Similarly, caveolar-dependence was determined by disrupting cellular lipid rafts with methyl-β-cyclodextrin. ETAR – AKT interaction was explored via Co-IP. Immunocytochemistry was used to determine if propofol was affecting the cellular localization of ETAR, Cav-1, AKT, or Cav-3. Cav-1 cellular localization was also investigated using discontinuous sucrose gradient fractionation.
Propofol-mediated-signaling (via pSTAT3 Y705 levels) was significantly reduced upon the inhibition of ETAR. In contrast, lipid raft disruption failed to reduce propofol-mediated-signaling. Propofol did not affect localization/ interaction of AKT. ETAR protein levels increased in intracellularly with propofol. Cav-1 protein expression/ localization did not change. However, Cav-3 levels did increase in the nuclear region with propofol treatment.
The results suggest that a component of propofol-signaling depends upon ETAR. Propofol signaling may act through a signalosome that involves receptor (ETAR) and Cav-3 internalization. This mechanism may be the avenue by which propofol is offering cardioprotection in a setting where other protection strategies are ineffective.Medicine, Faculty of
Anesthesiology, Pharmacology and Therapeutics, Department of
Graduate
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Organ, Leonard R. "Novel phosphorylation of Troponin I may cause the cardioprotective effects induced by isoproterenol." Thesis, National Library of Canada = Bibliothèque nationale du Canada, 2001. http://www.collectionscanada.ca/obj/s4/f2/dsk3/ftp04/MQ55923.pdf.
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Crowe, Sarah Lynn. "Cardioprotective effects of dihydropyridine antagonists in a murine model of chronic iron-overload." Thesis, National Library of Canada = Bibliothèque nationale du Canada, 2002. http://www.collectionscanada.ca/obj/s4/f2/dsk3/ftp05/MQ65615.pdf.
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Giehl, Esther [Verfasser]. "Cardioprotective effect of Polycystin 2 revealed in Isoproterenol-induced cardiac hypertrophy / Esther Giehl." Lübeck : Zentrale Hochschulbibliothek Lübeck, 2019. http://d-nb.info/1182589529/34.
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Pong, Terrence Kwok Cay. "Nitric Oxide and Postconditioning: Cardioprotective Methods for Acute Care of Ischemia Reperfusion Injury." Thesis, Harvard University, 2012. http://dissertations.umi.com/gsas.harvard:10540.
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Timely coronary artery reperfusion is essential to prevent myocyte death following myocardial infarction. The act of restoring blood flow however, paradoxically reduces the beneficial effects of reperfusion. This phenomenon, termed myocardial reperfusion injury, refers to the injury of cardiac myocytes that were viable immediately before reperfusion. Recent studies have shown that the timing and hemodynamic sequence of events which govern reperfusion can help to minimize the severity of reperfusion injury. The term postconditioning describes a modified form of reperfusion that involves a series of flow interruptions which confer significant cardioprotection to the heart. This thesis investigates ischemic postconditioning and endothelial nitric oxide synthase (eNOS) phosphorylation as cardioprotective therapies against reperfusion injury. In the first half of this thesis, we test the hypothesis that phosphorylation of eNOS serves as a cardioprotection nodal point for ischemic postconditioning. We show that phosphorylation of eNOS increases enzyme activity and that its product, nitric oxide, plays a critical role in cardioprotection. A number of cardiac dysfunctions arise after reperfusion and we address the effects of postconditioning on infarct size and myocardial blood flow. The second half of this thesis introduces the use of magnetic relaxometry sensors to detect cardiac biomarkers. The ability to non-invasively measure infarct size in small animals would be helpful in studying models of myocardial ischemia-reperfusion injury. We investigate the use of implantable biosensors in vivo and show that the cumulative detection of cardiac biomarkers correlates with infarct severity.Engineering and Applied Sciences
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Williams, Helen. "The transport and cardioprotective action of glutamate and aspartate in isolated ventricular myocytes." Thesis, University of Bristol, 1999. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.299276.
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Nagao, Kazuya. "Neural cell adhesion molecule is a cardioprotective factor up-regulated by metabolic stress." Kyoto University, 2010. http://hdl.handle.net/2433/120575.
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Gregg, Alison Dianne. "The design and synthesis of potential dual action cardioprotective agents acting at adenosine receptors." Queensland University of Technology, 2006. http://eprints.qut.edu.au/16629/.
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Adenosine and adenosine analogues are recognised as cardioprotective agents due to the responses that they induce through the activation of myocardial adenosine receptors. Antioxidants such as nitroxide radicals have also been found to possess cardioprotective properties in biological systems, namely through their ability to scavenge the oxygen-based free radicals that are potentially damaging to tissues and cells. It was envisaged that the linking of an antioxidant moiety to adenosine would produce an adenosine analogue that activates adenosine receptors and also scavenges oxygen-derived free radicals in the body. Consequently, one aim of this project was to synthesise a series of adenosine analogues that possessed a nitroxide or a phenolic antioxidant at the N6 position of the adenosine skeleton.
Allosteric ligands have several advantages over orthosteric ligands as potential therapeutic agents, and research into the allosteric enhancement of adenosine receptors is a burgeoning field. It was envisaged that the linking of an antioxidant moiety to an allosteric enhancer would produce a compound that enhances the response of endogenous activation of adenosine receptors and also scavenges oxygen-based free radicals in the body. Consequently, a second aim of this project was to synthesise a series of allosteric enhancers of the A1 adenosine receptor that possessed antioxidant capability endowed by a nitroxide or a phenolic antioxidant functionality.
This project has resulted in the synthesis and characterisation of 19 novel N6 substituted adenosine analogues, and additionally 12 novel derivatised thiophenes. Each of the target compounds was tested for its ability to bind to each of the adenosine receptor subtypes and some analogues were found to be potent and selective adenosine receptor agonists.
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Baydoun, A. R. "An investigation of the role of mitochondria in the cardioprotective action of calcium agonists." Thesis, University of Sunderland, 1988. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.383684.
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Suri, Ajay. "Factors affecting the cardioprotective response to remote ischaemic preconditioning in patients undergoing cardiac surgery." Thesis, University College London (University of London), 2017. http://discovery.ucl.ac.uk/10039417/.
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Death from ischaemic heart disease (IHD) remains the most common cause of death worldwide, and is also a significant cause of morbidity. Coronary artery bypass graft (CABG) surgery is performed in a significant number of IHD patients that meet certain clinical and angiographic criteria or are unsuitable for percutaneous coronary intervention. Increasingly higher risk surgeries are taking place, as the population survives to become more aged with well-managed co-morbidities. As such, the myocardium is at risk of peri-operative myocardial injury (PMI) during CABG surgery, the presence of which impacts on clinical outcomes. There are a number of strategies already in place to protect the myocardium during CABG surgery including therapeutic hypothermia, and the use of cardioplegic solutions, but there is a need to increase cardioprotection especially in higher-risk patients. In this regard, remote ischaemic conditioning (RIPC) is a promising, yet simple and cheap, non-invasive intervention, which shows huge promise in reducing PMI during CABG surgery. RIPC involves the serial inflations and deflations of a blood pressure cuff to the upper and/or lower limbs to induce brief cycles of ischaemia and reperfusion to the skeletal muscle. Despite the promise, clinical studies have produced variable results RIPC in the setting of CABG surgery, with confounding factors such as co-morbidities (age and diabetes) and comedications (propofol and glyceryl trinitrate) being proposed to interfere with the cardioprotective effect. In two separate clinical studies of adult patients undergoing CABG surgery, we investigated the effect of diabetes and glyceryl trinitrate (GTN) on the cardioprotective effect elicited by RIPC. We used an intensified RIPC protocol comprising 3 cycles of simultaneous inflation and deflation of two cuffs – one placed on the upper arm and the other on the thigh. The primary outcome measures of both clinical studies, was the extent of peri-operative myocardial injury (PMI), as evidenced by the 72 hours serum Troponin T area-under-the-curve. Secondary outcomes measures included the incidence of post-operative atrial fibrillation, acute kidney injury, inotrope score and length of intensive care and hospital stay. In the diabetic study, we found that RIPC significantly reduced the extent of PMI, whereas in the GTN study, RIPC resulted in only a non-significant reduction in PMI, when compared to control. There were no differences in the secondary outcome measurements with RIPC versis control in either study. In conclusion, we have demonstrated that intensifying the RIPC stimulus can overcome the confounding effects of diabetes and GTN on RIPC cardioprotection in patients undergoing CABG surgery.
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King, Jonathan Chan. "Cardioprotective role of signal transducer activator of transcription 3 (STAT-3) against ischaemai reperfusion injuries." Master's thesis, University of Cape Town, 2011. http://hdl.handle.net/11427/12692.
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Introduction: Sphingosine 1 phosphate (S1P) is a major constituent of high density lipoprotein (HDL) cholesterol. Both S1P preconditioning and ischaemic postconditioning reduce myocardial damage following an ischaemia-reperfusion insult but the mechanisms involved remain unclear. Janus kinase/Signal transducer and activator of transcription 3 (JAK/STAT-3) form part of a recently discovered powerful prosurvival path termed as the Survivor Activating Factor Enhancement (SAFE) pathway. The SAFE pathway plays a critical role in ischaemic preconditioning to promote cell survival but whether activation of STAT-3 is required for S1P preconditioning and ischaemic postconditioning induced cardioprotection is unknown. Hypothesis: Activation of the STAT-3 is required for S1P preconditioning and ischaemic postconditioning.
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Siu, Ada Hoi Ling. "Cardioprotective effects of herba cistanche on ischemia/reperfusion injury ex vivo and oxidative injury in vitro /." View abstract or full-text, 2008. http://library.ust.hk/cgi/db/thesis.pl?BICH%202008%20SIU.
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Ma, Yan, and 馬妍. "Role of the Ca2+ / calmodulin-dependent protein kinase II pathway in the cardioprotective effect of estrogen." Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2008. http://hub.hku.hk/bib/B41290744.
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Walsh, Sarah K. "Studies on the role of mast cell degranulation in mediating the cardioprotective effects of endothelin-1." Thesis, Robert Gordon University, 2007. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.436353.
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Whittington, H. J. "The influence of age and type 2 diabetes on cardioprotective interventions against myocardial ischaemia-reperfusion injury." Thesis, University College London (University of London), 2013. http://discovery.ucl.ac.uk/1402476/.
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The background of the thesis is based on the conflicting results between bench and bedside regarding the susceptibility to myocardial infarction with old age and diabetes. In laboratories all over the world, strategies have been developed to protect the myocardium from this insult, including the use of ischaemic conditioning (short periods of ischaemia and reperfusion prior to or following lethal ischaemia) or the use of a variety of pharmacological agents. However, surprisingly, translating these effective cardioprotective treatments into the clinic has proved problematic. The main issue seems to be the fact that the experimental investigations have mainly used young, healthy animals while the human patients present often with a number of other risk factors, or comorbidities, such as type 2 diabetes and old age. Therefore the aim of this thesis was to investigate the susceptibility to ischaemia-reperfusion injury and the proficiency of cardioprotective strategies to protect the heart in the setting of ageing and type 2 diabetes. Utilizing a model of type 2 diabetes, the Goto-Kakizaki rat and its normoglycaemic control Wistar rat, within the range of 3 to 18 months of age, the Langendorff isolated heart model and in vivo coronary artery occlusion and reperfusion were employed to investigate the susceptibility to ischaemia-reperfusion injury. Mechanical or pharmacological cardioprotective strategies were also investigated in this setting and the mechanisms of the failed cardioprotection were examined further using in vitro techniques focusing on known pro survival signalling pathways within the myocardium. The ageing diabetic heart demonstrated an increased vulnerability to injury and was less amenable to protection by ischaemic conditioning. Pharmacological agents namely, metformin and sitagliptin appear to differentially protect the diabetic and non-diabetic heart, and this could be due to the underlying intracellular changes associated with ageing and diabetes.
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Ma, Yan. "Role of the Ca2+ / calmodulin-dependent protein kinase II pathway in the cardioprotective effect of estrogen." Click to view the E-thesis via HKUTO, 2008. http://sunzi.lib.hku.hk/hkuto/record/B41290744.
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Morrison, Lisa E. "A cardioprotective role for the small heat shock protein, alpha B-crystallin, in ischemia-reperfusion injury /." Diss., Connect to a 24 p. preview or request complete full text in PDF format. Access restricted to UC campuses, 2003. http://wwwlib.umi.com/cr/ucsd/fullcit?p3112973.
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Välimäki, M. (Mika). "Discovery of cardioprotective isoxazole-amide compounds targeting the synergy of transcription factors GATA4 and NKX2-5." Doctoral thesis, M. Välimäki, 2018. http://urn.fi/urn:isbn:9789529412525.
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Abstract Acute myocardial infarction is a life-threatening condition that occurs as a result of reduced blood flow in the cardiac muscle, eventually leading to tissue damage. In infarcted areas, cardiomyocytes have insufficient ability to proliferate and replace the injured cells, which is associated with a deficient pumping capacity. A strictly regulated combinatorial interplay of transcription factors, e.g., GATA4, NKX2-5, TBX5, and MEF2C, orchestrates cardiac type gene expression during the cardiomyocyte differentiation and maturation processes. The aim of the present study was to (i) characterize the protein-protein interaction of the cardiac transcription factors GATA4-NKX2-5, (ii) evaluate the chemical agents that modify the synergy of GATA4-NKX2-5 in vitro, (iii) examine the capacity of the lead compound to promote myocardial repair in vivo after myocardial infarction and other cardiac injuries and (iv) study the structural features of the compound important for metabolism and cytotoxicity. Integration of the experimental mutagenic data with computational modeling suggests that the structural architecture of the GATA4-NKX2-5 interaction resembles the protein structure of the conserved DNA binding domain of nuclear receptors. Fragment-based screening, reporter gene-based optimization and pharmacophore searching were utilized to identify the most potent lead compound targeting the GATA4-NKX2-5 interaction: N-[4-(diethylamino)phenyl]-5-methyl-3-phenylisoxazole-4-carboxamide. This compound presented anti-hypertrophic effects in vitro and cardioprotective effects in vivo. In addition, structural analysis of the lead compound revealed the signature molecular features for metabolism and cytotoxicity. Current drug treatments are able to delay, but not prevent the progress of the heart failure; therefore, modulators of protein-protein interactions of key transcription factors may represent a novel class of pharmaceuticals for cardiac remodeling and repairTiivistelmä Sydäninfarkti on henkeä uhkaava verenkierron häiriö, joka syntyy veren virtauksen äkillisen vähentymisen seurauksena sydänlihaksessa aiheuttaen kudosvaurion. Vaurioituneen sydänlihaskudoksen kyky uusiutua tai korvata kuolleet sydänlihassolut uusilla on puutteellinen, ja tämän seurauksena sydämen pumppauskyky heikkenee. Transkriptiotekijöiden GATA4, NKX2-5, TBX5 ja MEF2C muodostamat ja koordinoimat proteiinikompleksit säätelevät sydänsolujen geenien ilmenemistä solujen elinkaaren aikana. Väitöskirjatyön tavoitteena oli (i) karakterisoida geeninsäätelytekijöiden GATA4-NKX2-5 molekyylirakenteet ja niiden keskinäinen vuorovaikutus, (ii) seuloa kemiallisia yhdisteitä, jotka muokkaavat GATA4-NKX2-5 proteiinikompleksin aikaansaamaa geeniaktivaatiota, (iii) tutkia johtoyhdisteen vaikutuksia in vivo sydäninfarktia ja painekuormitusta kuvaavissa eläinmalleissa, ja (iv) tutkia johtoyhdisteen molekyylirakenteen yhteyttä yhdisteen metaboliaan ja sytotoksisuuteen. Väitöskirjatyö osoittaa molekyylimallinuksen ja kokeellisten tulosten perusteella, että geeninsäätelytekijöiden GATA4-NKX2-5 proteiinikompleksin orientaatio matkii tumareseptoriperheen DNA domeenin tertiäärirakennetta. Molekyylifragmenttien, lusiferaasi-reportterikokeen ja farmakoforimallin avulla seulottiin ja optimoitiin sitoutumisvoimakkuudeltaan lupaavin GATA4-NKX2-5 proteiinikompleksin toimintaan vaikuttava johtoyhdiste: N-[4-(dietyyliamino)fenyyli]-5-metyyli-3-fenyyli-isoksatsoli-4-karboksamidi. Johtoyhdisteellä havaittiin solu- ja eläinmalleissa hypertrofiaa estäviä vaikutuksia in vitro ja sydäntä suojaavia vaikutuksia in vivo. Väitöskirjatyö osoitti lisäksi aktiivisten molekyylien rakenneominaisuuksia, jotka keskeisesti vaikuttavat yhdisteiden metaboliaan ja sytotoksisuuteen. Nykyinen lääkehoito hidastaa, mutta ei pysäytä sydänlihasvaurioon liittyvän kroonisen sydämen vajaatoiminnan etenemistä. Lääkevaikutuksen kohdentaminen sydämen keskeisten transkriptiotekijöiden yhteisvaikutukseen avaa uuden mahdollisen tutkimuslinjan sydänlihasvaurion estossa ja korjauksessa
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Jenner, Tamsin. "Adenosine Receptors in the Rat Heart: Effects of Age on Gene Expression and Functional Responses." Thesis, Griffith University, 2006. http://hdl.handle.net/10072/365966.
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Adenosine and adenosine receptors are important cardioprotective mediators. Age-related functional changes have previously been observed but factors that are likely to contribute remain unclear. This thesis examined the effect of age on (1) the mRNA expression of the ADOR and signalling molecules in whole heart and thoracic aorta preparations (chapter 3), and (2) the functional responses of the ADORA1, ADORA2B and ADORA3 in the rat heart (chapters 4-6). Quantitative real time PCR was employed to examine the effect of age on mRNA expression of the adenosine receptors (ADOR) and signalling messengers in hearts and thoracic aorta isolated immature (6-8 weeks), young (16-18 weeks), mature (52-54 weeks) and aged (104-106 weeks) rats, while protein expression of G?s-protein and Ca-L was examined using western blot. Conscious systolic blood pressure (sBP) was also measured in normotensive rats to demonstrate physiological variations that occur with maturation and ageing. Q-PCR analysis showed reduced mRNA expression of the ADORA1 with maturation but a 2.8-fold increase with ageing. In contrast, there was no detectable expression of the ADORA1 in isolated thoracic aorta. The ADORA2A, ADORA2B and ADORA3 were found to be expressed in hearts and thoracic aorta. In hearts they remained unchanged with maturation but were up-regulated (311, 317 and 309-fold, respectively) in aged rats. In thoracic aorta, the ADORA2A remained unaffected by age while the ADORA2B and ADORA3 were up-regulated in aged rats. In addition, up-regulation of the ADOR, NOS, Gi- and Go-proteins correlated with down-regulation of RyR and Ca-L and AC6. G7alpha;s-protein and Ca-L protein expression increased in young hearts, then decreased with maturation and ageing. Conscious systolic blood pressure increased from 98±1mmHg at 6 weeks to 134±5mmHg at 16 weeks (P less than 0.05), decreased to 85±4mmHg until 54 weeks and gradually increased again to 90mmHg by 104 weeks. The results indicate that cellular signalling systems in the rat heart change with maturation and ageing; while changes in the cardiac expression of the ADORA1, Gi2-, Gi3- and Gq-proteins, AC6, and NOS3 potentially play a role in age-related physiological changes in systolic blood pressure. The effect of age on ADORA1 mediated vascular, inotropic and chronotropic functional responses in rat isolated heart was examined in chapter 4. NECA (5`-(N-ethylcarboxamido)adenosine) and R-PIA (R-N6-(1-methyl-2-phenylethyl)adenosine) concentration-response curve experiments were conducted in Langendorff prepared hearts isolated from immature, young and mature male Wistar rats, and the effects of DPCPX (ADORA1 antagonist, 8-cyclopentyl-1,3-dipropylxanthine, 30nM) and PTX pre-treatment (48h, 10µg/kg IP, inhibits Gi/o-protein) were observed. NECA mediated coronary vasodilation and induced a biphasic concentration-response curve in hearts from immature rats (pEC50 8.5 (8.1-8.9) and 11.3 (10.3-12.3)). At the low-sensitivity site, NECA potency increased in young but not mature rats and remained unchanged at the high-sensitivity site. DPCPX blocked NECA at the high sensitivity site in immature rats, producing a monophasic concentration-response curve (pEC50 8.6 (8.5-9.9)), but not in young and mature rats. A monophasic response to NECA was produced in PTX pre-treated immature hearts (pEC50 8.7 (8.3-9.0)) with a vasoconstrictor response at lower agonist concentrations, which disappeared with age and was inhibited by DPCPX. No age-related changes were observed in R-PIA mediated negative inotropic and chronotropic responses (Pless than 0.05). According to the results, ADORA1 causes vasoconstriction of coronary resistance vessels via a PTX-insensitive pathway and induces vasodilation in hearts from immature rats; responses that decline with age. This study also investigated ADOR subtype activity and the role of Gi-protein and NO signalling in NECA mediated responses, and determined the effects of maturation on these responses (chapter 5). NECA concentration-response curves were determined in hearts from each age group. The effect of selective antagonists, including MRS1191 (ADORA3), alloxazine (ADORA2B), pertussis toxin (Gi-protein) and L-NAME (NOS) were determined in each group. NECA produced a biphasic response in hearts from immature rats with pEC50 values of 11.4 (10.4-12.4) and 8.5 (8.1-8.9), respectively, with no age-related changes detected (P up to 0.05). MRS1191 (200nM) decreased the potency of NECA at the high sensitivity site in immature but not young, mature and aged rats (P up to 0.05), while alloxazine (3µM) shifted the low sensitivity phase to the right 8 fold, 83 fold, 35 fold and 12 fold in hearts from each age group (P less than 0.05). Pertussis toxin pre-treatment inhibited the first phase of the concentration-response curve in immature rats, instead a vasoconstrictor response was observed. The vasoconstrictor response was reduced with age and a vasodilator response maintained in young and mature rats. L-NAME (3µM) induced a monophasic concentration-response curve to NECA with a vasoconstrictor response at the lowest doses, while the low sensitivity site remained unchanged. The results show that NECA mediates a heterogenous coronary vascular response. Vasodilator responses at the low sensitivity site are mediated by the ADORA2B and increase with maturation. This site remains unaffected by nitric oxide synthase inhibition therefore is likely to be localized to the vascular smooth muscle. It is also not affected by PTX, indicating no role for Gi-protein signalling, as expected. The effect of maturation and ageing on ADORA3 mediated coronary responses was investigated using isolated hearts perfused in Langendorff mode in chapter 6. APNEA (ADORA3 up to ADORA1 agonist) was observed to activate at least two receptor subtypes to mediate a biphasic vasodilator response in hearts from immature rats. The potency of APNEA at the high sensitivity site was enhanced by alloxazine (ADORA2B antagonist) and reduced when combined with MRS1191 (ADORA3 antagonist). This indicates that the high sensitivity phase is the ADORA3, and ADORA2B signalling is likely to play a negative regulatory role towards the ADORA3 mediated response. The activity at this site was also reduced with maturation. The low sensitivity site was inhibited by alloxazine but not MRS1191, indicating that this response is mediated by the ADORA2B or another receptor subtype. The response at this site did not alter with age. Cl-IB-MECA, (ADORA3 agonist) produced monophasic responses that were inhibited by alloxazine but remained unaffected by MRS1191 in all age groups. In addition the potency of Cl-IB-MECA does not change in hearts from PTX-treated rats. However, the maximal responses increased, indicating Gi-protein independent and dependent signalling. Q-PCR analysis of rat hearts indicated the presence of an ADORA3 splice variant (ADORA3i), which increased in mRNA expression with age. Cl-IB-MECA responses may be mediated by this ADORA3i. In summary, APNEA mediates coronary vasodilation in the rat heart via at least two receptor sites, the ADORA3 and ADORA2B. ADORA3 responses are reduced while ADORA2B remain unchanged with maturation. In addition, the splice variant ADORA3i may contribute to coronary responses in the rat heart. To summarize, this project investigated the gene expression and functional responses of the ADOR's in the cardiovascular system of the rat. All four ADOR subtypes are expressed in cardiac tissue, while only ADORA2A, ADORA2B and ADORA3 mRNA are expressed in isolated thoracic aorta. Pharmacological studies revealed that cardiac ADORA1 mediated responses do not change with age. In addition, the ADORA1, ADORA2B and ADORA3 mediate coronary vasodilator responses in hearts from immature rats, However, with advancing age, there is a change in the receptor population that mediates the vascular response, which involves the ADORA2B, ADORA3 and another unidentified receptor. Finally, the ADORA1 mediates a vasoconstrictor response, which is lost with age.Thesis (PhD Doctorate)
Doctor of Philosophy (PhD)
School of Medical Science
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Padua, Raymond Ronald. "The cardioprotective effects of fibroblast growth factor-2 against ischemia-reperfusion injury in the isolated rat heart." Thesis, National Library of Canada = Bibliothèque nationale du Canada, 1998. http://www.collectionscanada.ca/obj/s4/f2/dsk2/ftp03/NQ32013.pdf.
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