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1
Zhang, Weimin, and 張為民. "Cardiac k-opioid receptor: multiplicity, regulation, signal transduction and function." Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 1997. http://hub.hku.hk/bib/B3123804X.
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Sitsapesan, R. "Opioid receptors and ischaemia-induced cardiac arrhythmias." Thesis, University of Strathclyde, 1986. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.381536.
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Tai, Kwok-keung, and 戴國強. "A study on the cardiac k-opioid receptors: function, binding properties & signal transduction." Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 1993. http://hub.hku.hk/bib/B31233211.
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Tai, Kwok-keung. "A study on the cardiac k-opioid receptors : function, binding properties & signal transduction /." [Hong Kong] : University of Hong Kong, 1993. http://sunzi.lib.hku.hk/hkuto/record.jsp?B13441863.
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Asghari, Parisa. "Dynamic distribution of ryanodine receptors in cardiac muscles." Thesis, University of British Columbia, 2014. http://hdl.handle.net/2429/50492.
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The focus of this thesis is to address the location and distribution of the type 2 Ryanodine Receptor (RyR2) in mammalian cardiac myocytes with respect to their function. These integral membrane proteins function as Ca²⁺-activated Ca²⁺ ion channels as well as a scaffold for a large number of signaling molecules that modulate the release of Ca²⁺ through the channel. The relative position of the RyR2 tetramers is therefore a critical determinant of their function.
To study this question, I have used a combination of immunofluorescence microscopy, transmission electron microscopy, and tomography to map the position of the tetramers in whole cells and in cell sections and have used tissue obtained from both rat and human hearts. Biochemical and physiological techniques were used to correlate structure with function.
I have found that RyR2s are located only in three regions: in couplons on the surface, transverse tubules and on most of the axial tubules. In all regions, most but not all of the RyR2s colocalize with the voltage-gated Ca²⁺ channel (Cav1.2), suggesting that they play a role in excitation-contraction coupling. Some RyR2 are colocalized with cavelin-3 and not with Cav1.2 and hypothesized that these ‘extra-couplonic’ RyR2 might be regulated by the multitude of signaling molecules associated with caveolin-3 to modulate Ca²⁺ release. Dual-tilt electron tomography produced en face views of both rat and human dyads, enabling a direct examination of RyR2 arrangement. Both species showed that tetramer packing was non-uniform containing a mix of checkerboard and side-by-side arrangements as well as isolated tetramers. Finally, I showed that the tetramers’ arrangement depended on the Mg²⁺ concentration and on their phosphorylation status; in low Mg²⁺ and after phosphorylation RyR2s were positioned in largely checkerboard arrangements while in response to high Mg²⁺ the tetramers were positioned largely side by side. These tetramer arrangements: side by side, mixed and checkerboard were associated with progressively increasing spark frequencies. The correlation between tetramer arrangement and spark frequency suggests that tetramer rearrangement may be another mechanism whereby physiological processes operate and provides potential new mechanisms by which the activity of RYR2, the dyad and cardiac contractility may be regulated.Medicine, Faculty of
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Crisp, Andrew John. "Cardiac ventricular receptors and the control of respiration." Thesis, University of Newcastle Upon Tyne, 1989. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.241355.
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Zhang, Weimin. "Cardiac k-opioid receptor : multiplicity, regulation, signal transduction and function /." Hong Kong : University of Hong Kong, 1997. http://sunzi.lib.hku.hk/hkuto/record.jsp?B19588999.
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卞勁松 and Jin-song Bian. "The role of protein kinase C upon K-opioid receptor stimulation in theheart." Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2000. http://hub.hku.hk/bib/B31239900.
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Klipp, Robert Carl. "Catecholamine Interactions with the Cardiac Ryanodine Receptor." PDXScholar, 2013. https://pdxscholar.library.pdx.edu/open_access_etds/1439.
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The cardiac ryanodine receptor (RyR2) is a Ca2+ ion channel found in the sarcoplasmic reticulum (SR), an intracellular membranous Ca2+ storage system. It is well known that a destabilization of RyR2 can lead to a Ca2+ flux out of the SR, which results in an overload of intracellular Ca2+; this can also lead to arrhythmias and heart failure. The catecholamines play a large role in the regulation of RyR2; stimulation of the Beta-adrenergic receptor on the cell membrane can lead to a hyperphosphorylation of RyR2, making it more leaky to Ca2+. We have previously shown that strong electron donors will inhibit RyR2. It is hypothesized that the catecholamines, sharing a similar structure with other proven inhibitors of RyR2, will also inhibit RyR2. Here we confirm this hypothesis and show for the first time that the catecholamines, isoproterenol and epinephrine, act as strong electron donors and inhibit RyR2 activity at the single channel level. This data suggests that the catecholamines can influence RyR2 activity at two levels. This offers promising insight into the potential development of a new class of drugs to treat heart failure and arrhythmia; ones that can both prevent the hyperphosphorylation of RyR2 by blocking the Beta;-adrenergic receptor, but can also directly inhibit the release of Ca2+ from RyR2.
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NAGATA, KOHZO, TOYOAKI MUROHARA, XIAN WU CHENG, SHOGO WATANABE, MASAAKI MIYACHI, MAYUKO OHTAKE, MIWA TAKATSU, et al. "Glucocorticoids Activate Cardiac Mineralocorticoid Receptors in Adrenalectomized Dahl Salt- Sensitive Rats." Nagoya University School of Medicine, 2014. http://hdl.handle.net/2237/19484.
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Owen, Laura Jean. "Modulation of the Cardiac Calcium Release Channel by Homocysteine Thiolactone." PDXScholar, 2014. https://pdxscholar.library.pdx.edu/open_access_etds/2071.
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Elevated levels in blood serum (≥10μmol/L) of the amino acid homocysteine is strongly correlated with the incidence of heart failure (HF). We present evidence that the cyclic thioester, homocysteine thiolactone (HTL), a metabolic product of homocysteine, irreversibly modifies proteins that regulate the contractile process in cardiac muscle. Two proteins found in the sarcoplasmic reticulum (SR), the Ca2+ pump (SERCA2), and the ryanodine receptor (RyR2), are responsible for controlling the cytosolic Ca2+ concentration and hence the contractile state of the heart. While both improper Ca2+ handling and elevated homocysteine levels have been considered bio-markers in HF, a direct connection between the two has not previously been made. We show that HTL reacts with lysine residues on RyR2, generating a Nε-homocysteine-protein, which results in carbonyl formation and a change in the Ca2+ sensitivity of RyR2. This is a new molecular mechanism linking elevated levels of Homocysteine, improper Ca2+ handling and heart failure. This work was supported by NIH 1 R41 HL105063-01 to J. Abramson and R. Strongin.
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Warrier, Sunita. "cAMP BIOSENSORS AND SPATIOTEMPORAL cAMP SIGNALING IN ADULT CARDIAC MYOCYTES." Case Western Reserve University School of Graduate Studies / OhioLINK, 2007. http://rave.ohiolink.edu/etdc/view?acc_num=case1175718415.
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Bian, Jin-song. "The role of protein kinase C upon K-opioid receptor stimulation in the heart /." Hong Kong : University of Hong Kong, 2000. http://sunzi.lib.hku.hk/hkuto/record.jsp?B21790863.
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Whitney, Marsha L. "Molecular control of skeletal myoblast proliferation for cardiac repair /." Thesis, Connect to this title online; UW restricted, 2003. http://hdl.handle.net/1773/8008.
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Nistala, Pallavi. "5-HT2B Receptor-mediated Cardiac Valvulopathy." VCU Scholars Compass, 2018. https://scholarscompass.vcu.edu/etd/5689.
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5-HT2B receptor agonism causes cardiac valvulopathy, a condition characterized by thickening of the heart valves and as a result, regurgitation of blood within the heart. The anti-obesity drug fenfluramine, which was originally prescribed as an anorectic, was withdrawn from the market due to causing cardiac valvulopathy. Fenfluramine, after metabolism by N-dealkylation, produces the metabolite norfenfluramine, which acts as a more potent valvulopathogen. The same was seen with MDMA (ecstasy), a popular drug of abuse, which is metabolized by N-dealkylation to produce MDA, a more potent valvulopathogen. Glennon and co-workers. studied a series of 2,5-dimethoxy-4- substituted phenylisopropylamines (DOX type) hallucinogens and determined their affinities at the three types of 5-HT2 receptors. A high correlation was found between the affinities of these molecules at 5-HT2A and 5-HT2B receptors. Therefore, these hallucinogens have a high possibility of causing valvulopathy, which gives rise to a new class of valvulopathogens.
Since certain hallucinogens have the common phenylisopropylamine structural scaffold as that of MDA and norfenfluramine, we conducted 3D-QSAR studies to identify the common structural features of these molecules that are responsible for their high affinities. We were unable to obtain a suitable CoMFA and CoMSIA model for 5-HT2B receptors, but we were able to obtain an internally and externally validated model for 5-HT2A receptor affinities which indicated the hydrophobicity of the substituent at the 4- position was essential for high affinity. Following up with this evidence, we conducted a correlation analysis for the hydrophobicity (π-value) of the 4-position substituent and found a positive correlation between the π-value and the affinity of the molecules. The same results were not observed for the volume of the substituents.
We docked the molecules into the 5-HT2B receptor and successfully generated models of the putative interactions made by the DOX molecules and the receptor. In order to compare their binding modes with respect to known valvulopathogens, we also generated models for norfenfluramine and MDA. Our docking results revealed that DOX molecules bind in a more or less similar manner to valvulopathogens MDA and norfenfluramine. Ours is the first in silico model developed for the potent valvulopathogen MDA and the hallucinogenic DOX series of molecules.
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Mattern, Janet. "Muscarinic Receptor Modulation of the Phospholipid Effect in Cardiac Myocytes." Thesis, North Texas State University, 1986. https://digital.library.unt.edu/ark:/67531/metadc500469/.
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The muscarinic agonist carbachol stimulates a rapid increase in ^32Pi incorporation into phosphatidic acid (PA) and phosphatidylinositol (PI) in calcium tolerant myocytes prepared from heart tissue. The density of muscarinic receptors, determined by [^3H]-QNB binding, is greater in the atria than in the ventricles. 250 uM carbachol decreased specific [^3H]-QNB binding to muscarinic receptors on myocyte membranes by fifty percent. Trifluoperazine, also a phospholipase C inhibitor, inhibited the carbachol stimulated increase in ^32Pi incorporation into PA and PI and did not interfere with muscarinic receptor binding. Therefore, isolated canine myocytes provide a suitable model system to further study the muscarinic receptor stimulated phospholipid effect, and its role in mediating biochemical processes and physiological function in the heart.
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Beauglehole, Anthony Robert, and anthony@adenrx com. "N3-substituted xanthines as irreversible adenosine receptor antagonists." Deakin University. School of Biological and Chemical Sciences, 2000. http://tux.lib.deakin.edu.au./adt-VDU/public/adt-VDU20080612.084330.
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8-Cyclopentyl-3-(3-(4-fluorosulfonylbenzoyl)oxy)propyl-propylxanthine (44, FSCPX) has been reported to exhibit potent and selective irreversible antagonism of the A1 adenosine receptor when using in vitro biological preparations. However, FSCPX (44) suffers from cleavage of the ester linkage separating the reactive 4-(fluorosulfonyl)phenyl moiety from the xanthine pharmacophore when used in in vivo biological preparations or preparations containing significant enzyme activity, presumably by esterases. Cleavage of the ester linkage renders FSCPX (44) inactive in terms of irreversible receptor binding. In order to obtain an irreversible A1 adenosine receptor antagonist with improved stability, and to further elucidate the effects of linker structure on pharmacological characteristics, several FSCPX (44) analogues incorporating the chemoreactive 4-(fluorosulfonyl)phenyl moiety were targeted, where the labile ester linkage has been replaced by more stable functionalites. In particular, ether, alkyl, amide and ketone linkers were targeted, where the length of the alkyl chain was varied from between one to five atoms.
Synthesis of the target compounds was achieved via direct attachment of the N-3 substituent to the xanthine. These compounds were then tested for their biological activity at the A1 adenosine receptor via their ability to irreversibly antagonise the binding of [3H]-8-cyclopentyl-1,3-dipropylxanthine ([3H]DPCPX, ( 9) to the A1 adenosine receptor of DDT1 MF-2 cells. For comparison, the xanthines were also tested for their ability to inhibit the binding of [3H]-4-(2-[7-amino-2-{furyl} {1,2,4}- triazolo{2,3-a} {1,3,5}triazin-5-ylamino-ethyl)]phenol ([3H]ZM241385, 36) to the A2A adenosine receptor of PC-12 cells. The results suggest that the length and chemical composition of the linker separating the reactive 4-(fluorosulfonyl)phenyl moiety from the xanthine ring contribute to the potency and efficacy of the irreversible A1 adenosine receptor ligands. Like FSCPX (44, IC50 A1 = 11.8 nM), all derivatives possessed IC50 values in the low nM range under in vitro conditions. Compounds 94 (IC50 A1 = 165 nM), 95 (IC50 A1 = 112 nM) and 96 (IC50 A1 = 101 nM) possessing one, three and five methylene spacers within the linkage respectively, exhibited potent and selective binding to the A1 adenosine receptor versus the A2A adenosine receptor. Compound 94 did not exhibit any irreversible binding at A1 adenosine receptors, while 95 and 96 exhibit only weak irreversible binding at A1 adenosine receptors. Those compounds containing a benzylic carbonyl separating the 4-(fluorosulfonyl)phenyl moiety from the xanthine ring in the form of an amide (119, IC50 A1 = 24.9 nM, and 120, IC50 A1 = 21 nM) or ketone (151, IC50 A1 = 14 nM) proved to be the most potent, with compound 120 exhibiting the highest selectivity of 132-fold for the A receptor over the A2A receptor. compounds 119, 120 and 151 also strongly inhibited the binding of [3H]DPCPX irreversibly (82%, 83% and 78% loss of [3H]DPCPX binding at 100 nM respectively). compounds 120 and 151 are currently being evaluated for use in in vivo studies.
Structure-activity studies suggest that altering the 8-cycloalkyl group of A1 selective xanthines for a 3-substituted or 2,3-disubstituted styryl, combined with N-7 methyl substitution will produce a compound with high affinity and selectivity for the A2A adenosine receptor over the A1 adenosine receptor. Compound 167 (IC50 A2A = 264 nM) possessing 8-(m-chloro)styryl substitution and the reactive 4-(fluorosulfonyl)phenyl moiety separated from the xanthine ring via an amide linker in the 3-position (as for 119 and 120), exhibited relatively potent binding to the A2A adenosine receptor of PC-12 cells, with a 16-fold selectivity for that receptor over the A1 adenosine receptor. However, compound 167 exhibited only very weak irreversible binding at A2A adenosine receptors.
Overall, at this stage of biological testing, compound 120 appears to possess the most advantageous characteristics as an irreversible antagonist for the A1 adenosine receptor. This can be attributed to its high selectivity for the A1 adenosine receptor as compared to the A2A adenosine receptor. It also has relatively high potency for the A1 adenosine receptor, a concentration-dependent and selective inactivation of A1 adenosine receptors, and unbound ligand is easily removed (washed out) from biological membranes. These characteristics mean compound 151 has the potential to be a useful tool for the further study of the structure and function of the A1 adenosine receptor.
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盛建中 and Jianzhong Sheng. "Phosphoinositol/Ca2+ pathway in the cardiac k-opioid receptor: physiological role and alternations upontolerance." Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 1997. http://hub.hku.hk/bib/B31237654.
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Ye, Yanping. "Designing New Drugs to Treat Cardiac Arrhythmia." PDXScholar, 2012. https://pdxscholar.library.pdx.edu/open_access_etds/638.
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Heart failure resulting from different forms of cardiomyopathy is defined as the inability of the heart to pump sufficient blood to meet the body's metabolic demands. It is a major disease burden worldwide and the statistics show that 50% of the people who have the heart failure will eventually die from sudden cardiac death (SCD) associated with an arrhythmia. The central cause of disability and SCD is because of ventricular arrhythmias. Genetic mutations and acquired modifications to RyR2, the calcium release channel from sarcoplasmic reticulum, can increase the pathologic SR Ca2+ leak during diastole, which leads to defects in SR calcium handling and causes ventricular arrhythmias. The mechanism of RyR2 dysfunction includes abnormal phosphorylation, disrupted interaction with regulatory proteins and ions, or altered RyR2 domain interactions. Many pharmacological strategies have shown promising prospects to modulate the RyR2 as a therapy for treating cardiac arrhythmias. Here, we are trying to establish a novel approach to designing new drugs to treat heart failure and cardiac arrhythmias. Previously, we demonstrated that all pharmacological inhibitors of RyR channels are electron donors while all activators of RyR channels are electron acceptors. This was the first demonstration that an exchange of electrons was a common molecular mechanism involved in modifying the function of the RyR. Moreover, we found that there is a strong correlation between the strength of the electron donor/acceptor, and its potency as a channel inhibitor/activator, which could serve as a basis and direction for developing new drugs targeting the RyR. In this study, two new potent RyR inhibitors, 4-methoxy-3-methyl phenol (4-MmC) and the 1,3 dioxole derivative of K201, were synthesized which are derivatives of the known RyR modulators, 4-chloro-3-methyl phenol (4-CmC) and K201. The ability of K201, 1,3 dioxole derivative of K201 and 4-MmC to inhibit the cardiac calcium channel is examined and compared at the single channel level. All of these compounds inhibited the channel activity at low micromolar concentrations or sub-micromolar concentrations.
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Omede, Ameh. "Role of alpha-ketoglutarate receptor G-protein coupled receptor 99 (GPR99) in cardiac hypertrophy." Thesis, University of Manchester, 2015. https://www.research.manchester.ac.uk/portal/en/theses/role-of-alphaketoglutarate-receptor-gprotein-coupled-receptor-99-gpr99-in-cardiac-hypertrophy(83b04dba-5bfe-4623-ade1-12c779133b80).html.
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Cardiac hypertrophy and heart failure (HF) remains one of the major health problems in the UK and worldwide. However, advances in their management are limited because the underlying pathological mechanisms are not completely understood. Therefore, it is important to understand novel signalling pathways leading to HF. Myocardial hypertrophy is a crucial pathophysiological process that can lead to the development of HF. Signalling initiated by members of G-protein-coupled receptors (GPCRs) proteins plays an important role in mediating cardiac hypertrophy. One member of this family, the G-protein coupled receptor 99 (GPR99), may have a crucial role in the heart because it acts as a receptor for alpha-ketoglutarate, a metabolite that is elevated in heart failure patients. GPR99 is expressed in the heart, but its precise function during cardiac pathophysiological processes is unknown. The aim of this PhD study is to investigate the role of GPR99 during cardiac hypertrophy. In this study I used in vivo and in vitro approaches to investigate whether GPR99 is directly involved in mediating cardiac hypertrophy. Mice with genetic deletion of GPR99 (GPR99-/-) exhibited a significant increase in hypertrophy following two weeks of transverse aortic constriction (TAC) as indicated by heart weight/tibia length ratio (HW/TL). In addition, GPR99-/- mice displayed increased cardiomyocytes cross-sectional area (CSA) after TAC compared to wild-type (WT) littermates. Hypertrophic markers such as brain natriuretic peptide (BNP) and β-myosin heavy chain (β-MHC) were also elevated in GPR99-/- mice following TAC compared to WT mice. Although interstitial fibrosis was indistinguishable in both genotypes after TAC, a precursor of fibrosis, collagen, type III, alpha1 (COL3A1) was elevated in GPR99-/- mice compared to WT mice after TAC. The baseline cardiac function as indicated by ejection fraction (EF) and fractional shortening (FS) were reduced in GPR99-/- mice compared to WT littermates following TAC. Furthermore, left ventricular end-diastolic diameter (LVEDD), left ventricular end-systolic diameter (LVESD), interventricular septum wall thickness (IVS) and posterior wall thickness at diastole (PW) indicated profound wall thickening and enlargement of the left ventricular (LV) chamber in GPR99-/- mice compared to WT littermates after TAC. In an attempt to examine the mechanism through which GPR99 signals during hypertrophy, I performed molecular analyses based on the data from yeast two hybrid screening showing that GPR99 interacted with COP9 signalosome element 5 (CSN5). Using immunoprecipitation assay, I found that GPR99 formed a ternary complex with CSN5 and non-receptor tyrosine kinase 2 (TYK2). TYK2 is known as a regulator of pro-hypertrophic molecules including signal transducer and activation of transcription 1 (STAT1) and STAT3. I found that the activation of these molecules was increased in GPR99-/- mice following TAC and correspondingly, adenovirus-mediated overexpression of GPR99 in neonatal rat cardiomyocytes (NRCM) blunted TYK2 phosphorylation. In conclusion, my study has identified GPR99 as a novel regulator of pathological hypertrophy via the regulation of the STAT pathway. Identification of molecules that can specifically activate or inhibit this receptor may be very useful in the development of a new therapeutic approach for cardiac hypertrophy in the future.
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Gu, Hong. "Opioid/Adrenergic Interaction in Regulating Canine Cardiac Function." Thesis, University of North Texas, 1990. https://digital.library.unt.edu/ark:/67531/metadc331004/.
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Opioid/adrenergic interactions were studied to evaluate two hypotheses: (1) naloxone potentiates the effect of epinephrine on cardiac contractility by increasing circulating epinephrine concentrations; and (2) endogenous and exogenous opioids alter left cardiac nerve stimulationinduced norepinephrine release and cardiac function. A canine isolated heart-lung preparation was used for the first study. Plasma epinephrine was determined and myocardial epinephrine uptake was calculated during intravenous epinephrine infusion. Naloxone (4 mg) was given and the epinephrine infusion was repeated. Naloxone increased cardiac contractility, coronary blood flow, and the coronary sinus epinephrine concentration. When coronary blood flow was subsequently held constant (100% above resting), naloxone increased only contractility. This result indicated that the previously observed increase in coronary sinus epinephrine was flow dependent. Corticosterone (an uptake II blocker) was employed as a positive control. Corticosterone increased the contractile response to epinephrine, but unlike naloxone, corticosterone was accompanied by a clear decrease in myocardial epinephrine uptake. The stereospecificity of the response to naloxone was investigated and (+) naloxone equaled or exceeded (-) naloxone in potentiating the inotropic effect of epinephrine. In the second study, the left cardiac nerve was isolated and electrically stimulated in intact dogs. Norepinephrine overflow gradually declined during successive control stimulations. Pretreatment with naloxone (100 Mg/kg) prevented or delayed the decline. An intracoronary dynorphin 1-9 infusion (2 nmol/min/kg for 20 minutes) reduced both norepinephrine overflow and cardiac performance, and both effects were prevented by pretreatment with naloxone (100 /xg/kg) . To summarize, naloxone potentiated the inotropic effect of infused epinephrine without altering circulating epinephrine concentrations or myocardial epinephrine uptake. This effect of naloxone was not stereospecific and probably not mediated through a traditional opiate receptor. Endogenous and exogenous opioids inhibited the left cardiac nerve stimulation-induced norepinephrine overflow, suggesting that opiate receptors may regulate cardiac excitability by modulating norepinephrine release.
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Vidal, Marie [Verfasser], and Kristina [Akademischer Betreuer] Lorenz. "b-adrenergic receptors and Erk1/2-mediated cardiac hypertrophy / Marie Vidal. Betreuer: Kristina Lorenz." Würzburg : Universitätsbibliothek der Universität Würzburg, 2013. http://d-nb.info/1043906363/34.
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Maxwell, Chloe. "Luminal accessory protein regulation of wild type and mutant human cardiac ryanodine receptors (hRyR2)." Thesis, Cardiff University, 2014. http://orca.cf.ac.uk/71291/.
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Human cardiac ryanodine receptors (hRyR2) are major Ca2+ release channels in the heart, which form quaternary complexes with luminal proteins, calsequestrin (CSQ2), junctin (JUN) and triadin (TRD1). These proteins facilitate Ca2+ release during excitation-contraction coupling, modulating the response of hRyR2 to luminal Ca2+ changes. Catecholaminergic Polymorphic Ventricular Tachycardia is an arrhythmogenic disorder, caused by mutations in RyR2 and CSQ2 genes. Defective sensing of cytosolic/luminal Ca2+ by hRyR2 is a candidate mechanism underlying disease pathogenesis, likely caused by defective luminal protein regulation. Using a recombinant approach, this study aimed to evaluate if mutant (N4104K and A4556T) hRyR2 respond to or interact differently with, these accessory proteins. Expression constructs corresponding to CSQ2 and JUN were generated and expressed stably and transiently with wild-type (WT) or mutant hRyR2 in HEK293 cells. Immunofluorescent co-localisation confirmed successful co-expression and association of these luminal proteins with hRyR2 in situ. Ca2+ activation of wild-type/mutant hRyR2 in the absence/presence of CSQ2 and/or JUN was assessed by [3H]-ryanodine binding, while luminal Ca2+ effects were monitored using single-cell Ca2+ imaging - examining spontaneous Ca2+ release events. A4556T-hRyR2 displayed similar cytosolic and luminal Ca2+ dependence to wild-type channels, whilst N4104K-hRyR2 displayed a remarkably different Ca2+ activation profile, demonstrating functional heterogeneity between hRyR2 mutants. Ca2+ imaging revealed an inhibitory effect of CSQ2 on WT and N4104K-hRyR2 activity, both in the presence and absence of JUN. In line with this, CSQ2 was found to bind directly to hRyR2 by co-immunoprecipitation, an observation that has not been previously demonstrated in the literature. Immunofluorescence studies suggested reduced CSQ2 and JUN association with A4556T-hRyR2, but this could not be confirmed with co-immunoprecipitation. Ca2+ imaging investigations with this mutant however, suggested that CSQ2 wasn’t able to regulate these channels in the same way as WT, implying a change in functional effect.
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Naase, Hatam. "The role of the Toll-like receptors in systemic inflammatory response to cardiac surgery." Thesis, Imperial College London, 2015. http://hdl.handle.net/10044/1/49222.
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Background: Cardiac surgery with cardiopulmonary bypass (CPB) can lead to a spectrum of post-operative complications as a result of activation of systemic inflammatory responses. Cellular injury can lead to the release of damage-associated molecular patterns (DAMPs) such as mitochondria DNA (mtDNA), which act as a ligand activating leukocytes and endothelial cells via innate immunity receptors such as Toll-like receptor 9 (TLR9). However, the contributions of DAMPs to inflammatory responses to CPB are unknown. Aim: This study is to identify the DAMPs and associated receptors that drive systemic inflammatory responses to surgery, which may lead to the identification of novel anti-inflammatory interventions such as TLR antagonists with subsequent translation of our findings to the clinical field. Additionally, Post-operative atrial fibrillation (POAF) is frequent complication in cardiac surgery, which may contribute to the inflammatory response. We aimed to identify a possible predictor for POAF, which may lead to its prevention or early management. Methods: Sixty-six patients undergoing CABG were recruited, 44 with on-pump and 22 with off-pump CABG (OPCAB) to compare the effect of CPB. To identify the effect of ischemic heart disease (IHD) on the mtDNA release. We recruited a separate group of 22 patients undergoing aortic valve replacement (AVR) with normal coronary angiogram. Blood samples were taken at different time-points to CPB. Quantitative PCR was generated to quantify mtDNA concentration (Chapter 3). Pro-inflammatory biomarkers such as interleukines, interferons, MAP kinases , NF-κB and other biomarkers were assessed by PCR array (Chapter 5). Both mtDNA and the proinflmmatory biomarker were preoperatively compared to assess of the development of POAF (Chapter 6). Additionally, we used different animal models experiments, to establish the effect of surgery and CPB on TLR9 signalling and to test the effect of blocking TLR9. Specifically, we performed sternotomy in mouse and rat models respectively and performed sternotomy with CPB in the pig model (Chapter 4). Results: mtDNA was significantly higher in patients with IHD than those without (p < 0.01). CABG with CPB led to a significant elevation in serum mtDNA levels compared to OPCAB (p < 0.001 at peak of CPB time). The potential downstream activation of TLR9 also showed significant elevation in all cytokines and chemokines utilizing the TLR9 signalling pathway (p varies from < 0.001 - < 0.05) but not those using other signalling pathway (p > 0.05). Blocking the TLR9 in mice has significantly reduced the production of proinflammatory cytokine (IL-6). INF-α and mtDNA were the only independent predictors for POAF development. Conclusion: Elevation in circulating mtDNA level is related to the extent of the IHD. CPB can influence the release of circulating mtDNA and proinflammatory cytokines production via signalling the TLR9, which may contribute to the initiation of a sterile systemic inflammatory response. The mtDNA and INF- α were independent predictors for development of POAF, which are in agreement with the inflammatory theory that relates the inflammation to the POAF development.
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Overn, Steven P. (Steven Paul). "Alpha-Adrenergic Modulation of Coronary Blood Flow and Cardiac Function During Exercise in Dogs." Thesis, North Texas State University, 1985. https://digital.library.unt.edu/ark:/67531/metadc935562/.
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In the present study alpha-receptor modulation of coronary flow and cardiac function was examined in exercising dogs, chronically instrumented to measure: circumflex blood flow velocity (CFV), heart rate (HR), global left ventricular function (LVP and dP/dt Max) and regional left ventricular function (%SL and dL/dt (s)max). During exercise, local adrenergic blockade was produced by intracoronary injection of 1.0 mg phentolamine ( anon-specific alpha-antagonist) or .5 mp prazosin. Exercise significantly increased HR, LVP, dP/dt max, CFV, %SL and dL/dt (s)max. Neither alpha-antagonist produced changes in HR, LVP or %SL; however, both phentolamine and prazosin produced significant increses in dP/dtmax, CFV and dL/dt(s)max of the alpha-blocked region, when compared to their exercise level before alpha-blockade. It is suggested that an alpha1-adrenergic vasoconstriction limits coronary vasodilation and, thereby, cardiac function during exercise.
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Gaboardi, Angela Kampfer. "Regulation of the cardiac isoform of the ryanodine receptor by S-adenosyl-l-methionine." Diss., Georgia Institute of Technology, 2011. http://hdl.handle.net/1853/42854.
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Activity of the Ryanodine Receptor (RyR2) (aka cardiac Ca2+ release channel) plays a pivotal role in contraction of the heart. S-adenosyl-l-methionine (SAM) is a biological methyl group donor that has close structural similarity to ATP, an important physiological regulator of RyR2. This work provides evidence that SAM can act as a RyR2 regulatory ligand in a manner independent from its recognized role as a biological methyl group donor. RyR2 activation appears to arise from the direct interaction of SAM, via its adenosyl moiety, with the RyR2 adenine nucleotide binding sites. Because uncertainty remains regarding the structural motifs involved in RyR2 modulation by ATP and its metabolites, this finding has important implications for clarifying the structural basis of ATP regulation of RyR2.
During the course of this project, direct measurements of single RyR2 activity revealed that SAM has distinct effects on RyR2 conductance. From the cytosolic side of the channel, SAM produced a single clearly resolved subconductance state. The effects of SAM on channel conductance were dependent on SAM concentration and membrane holding potential. A second goal of this work was to distinguish between the two possible mechanisms by which SAM could reduce RyR2 conductance: i) SAM interfering directly with ion permeation via binding within the conduction pathway (pore block), or ii) SAM binding a regulatory (or allosteric) site thereby stabilizing or inducing a reduced conductance conformation of the channel. It was determined that SAM does not directly interact with the RyR2 conduction pathway.
To account for these observations an allosteric model for the effect of SAM on RyR2 conductance is proposed. According to this model, SAM binding stabilizes an inherent RyR2 subconductance conformation. The voltage dependence of the SAM related subconductance state is accounted for by direct effects of voltage on channel conformation which indirectly alter the affinity of RyR2 for SAM. Patterns in the transitions between RyR2 conductance states in the presence of SAM may provide insight into the structure-activity relationship of RyR2 which can aid in the development of therapeutic strategies targeting this channel.
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Kaur, Gurpreet. "Latency and G protein-sensitive heterogeneity in reconstituted cardiac muscarinic receptors, implications for co-operativity." Thesis, National Library of Canada = Bibliothèque nationale du Canada, 2000. http://www.collectionscanada.ca/obj/s4/f2/dsk1/tape2/PQDD_0024/MQ50452.pdf.
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Zheng, Jing-Sheng. "ATP receptors and regulation of the ATP-induced calcium ion mobilization response in cardiac myocytes." Case Western Reserve University School of Graduate Studies / OhioLINK, 1992. http://rave.ohiolink.edu/etdc/view?acc_num=case1056573774.
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Murphy, Cody. "Transregulation of Cardiac Ischaemic Tolerance and Stress Kinase Signalling by A1 Adenosine and ¿-Opioid Receptors." Thesis, Griffith University, 2018. http://hdl.handle.net/10072/382690.
Full textAbstract:
Protecting hearts from damage sustained during myocardial ischaemia and reperfusion remains an ongoing challenge. Despite successful findings with animal models, the task of trialling and effectively translating experimental findings from laboratory to patients has proven difficult, therefore treatments and clinical therapies are still urgently needed to protect the heart and improve cardiac functional outcome. Previous research has implicated adenosine and opioid receptor participation in the protective response preceding or following myocardial infarction, with evidence of potential cross-talk between receptors. This project aimed to investigate whether A1 adenosine (A1AR) and δ-opioid receptor (δ-OR) dependent cytoprotection and prosurvival kinase activation in murine hearts share common dependencies on „cross-talk‟ between both G-protein coupled receptor (GPCR) sub-types and whether these responses involve a common Matrix Metalloproteinase (MMP) and Epidermal Growth Factor Receptor (EGFR) dependent signalling pathway. This was achieved via four inter-related in vitro studies.
Study 1: Healthy mouse hearts were cannulated in a Langendorff mode enabling the coronary circulation to be perfused. Hearts were subjected to 25 minutes of global (zero-flow) ischaemia followed by 45 minutes of aerobic reperfusion. The groups investigated included untreated control hearts, hearts receiving the selective A1AR agonist CCPA (± DPCPX, a selective A1AR antagonist, or BNTX, a selective δ-OR antagonist) and hearts receiving the selective δ-OR agonist BW373U86 (± DPCPX, a selective A1AR antagonist, or BNTX, a selective δ-OR antagonist). Agonists were applied 5 minutes pre-ischaemia and the antagonists were administered 10 minutes prior to agonist treatment. Cardiac functional outcomes were assessed via changes in coronary flow, left ventricular (LV) end diastolic pressure and pressure development, and ±dP/dt (± differentials of pressure change with time – indexing lusitropic and inotropic state). Cell death outcomes were also assessed via lactate dehydrogenase (LDH) release.
Treatment with either the selective A1AR agonist CCPA, or the selective δ-OR agonist BW373U86, significantly reduced (p≤0.0001 vs. CTRL) LV end-diastolic pressure following ischaemia/reperfusion. Recovery of LV developed pressure (LVDP) was significantly increased following A1AR activation via CCPA (p≤0.0001 vs. CTRL) or δ-OR activation via BW373U86 (p≤0.001 vs. CTRL). Ventricular contractility
(+dP/dt) and relaxation (-dP/dt) were also significantly improved with both CCPA (p≤0.0001 vs. CTRL, p≤0.01 vs. CTRL) and BW373U86 (p≤0.001 vs. CTRL, p≤0.001 vs. CTRL). Treatment with CCPA, but not BW373U86, significantly improved the recovery of coronary flow rate at the termination of reperfusion (p≤0.01 vs. CTRL).
LDH release (corresponding to cell death) was significantly reduced by both CCPA and BW373U86 (p<0.05 vs. CTRL, p<0.05 vs. CTRL). A1AR or δ-OR inhibition, via the selective antagonists DPCPX and BNTX respectively (applied alone), did not significantly affect the recovery of functional outcomes or cell death relative to control. These results show that cardioprotection against ischaemic injury is induced with activation of A1ARs and δ-ORs, and that endogenous levels of receptor agonists may not be sufficient to induce this response. Protection with CCPA was abolished via cotreatment with either the selective A1AR antagonist DPCPX or the selective δ-OR antagonist BNTX. Conversely protection with BW373U86 administration was negated by co-treatment with either BNTX or DPCPX. This reveals that A1AR dependent cardioprotection is reliant on the activation of δ-ORs, and δ-OR mediated protection is dependent on A1AR activity, confirming essential cross-talk.
Study 2: Perfused hearts from study 1 were snap-frozen in liquid nitrogen following the termination of reperfusion. Hearts were homogenised and fractioned to yield cytosolic proteins. Total and phosphorylated levels of Erk1/2 and Akt were subsequently assessed via western immunoblot. Both A1AR and δ-OR stimulation via CCPA and BW373U86 (respectively) did not significantly influence Erk1/2 phosphorylation. Akt phosphorylation, on the other hand, was increased by both CCPA and BW373U86; although only the latter effect achieved statistical significance (p<0.01 vs. CTRL). The A1AR antagonist DPCPX had minimal effect on Erk1/2 and Akt phosphorylation when applied alone. Alternatively inhibition of the δ-OR via BNTX, applied alone, was found to increase both Akt and Erk1/2 phosphorylation, a response in conflict with the existing literature.
Co-treatment with the A1AR antagonist DPCPX or the δ-OR antagonist BNTX did not significantly influence Erk1/2 signalling compared to controls. Alternatively Akt phosphorylation was reduced by ~50% relative to control when hearts were co-treated with DPCPX or BNTX applied in conjunction with either the A1AR agonist CCPA or the δ-OR agonist BW373U86. These results imply that both A1ARs and δ-ORs together are necessary to induce protective Akt signalling during ischaemia/reperfusion with either receptor agonist.
Study 3: To assess the roles of EGFRs and MMPs in A1AR and δ-OR responses, agonist studies with CCPA and BW373U86 were repeated with co-treatment with the EGFR antagonist AG1478 or the MMP inhibitor GM6001. Functional and cytoprotective outcomes were assessed in perfused hearts subjected to ischaemiareperfusion. The protective response observed with either A1AR and δ-OR stimulation was negated via co-treatment with either AG1478 or GM6001. A1AR and δ-OR dependent recovery of end diastolic pressure, LV developed pressure, +dP/dt and -dP/dt were all repressed via EGFR or MMP inhibition. Moreover, the cytoprotective response conferred by δ-OR activation was completely abolished via co-treatment with AG1478 or GM6001, providing evidence that adenosinergic and opioidergic protection within the myocardium involves an EGFR and MMP dependent pathway.
Study 4: Western blot analysis was used to assess changes in Erk1/2 and Akt expression and phospho-regulation in hearts treated with CCPA or BW373U86 in the presence of AG1478 or GM6001. Due to time constraints, data collected previously in our lab was used in this research; therefore the effect of EGFR and MMP inhibition on A1AR dependent Erk1/2 and Akt signalling was assessed in whole heart rather than cytosolic fractions. In these hearts, administration of CCPA significantly elevated both
Erk1/2 and Akt phosphorylation, a response negated via co-treatment with either
AG1478 or GM6001 (p≤ 0.05 vs. CCPA). Infusion of the selective δ-OR agonist BW373U86 did not significantly alter Erk/1/2 expression or phosphorylation in cytosolic fractions. Despite this, co-treatment with AG1478 reduced Erk1/2 phosphorylation by ~50% compared to the agonist alone (p ≤ 0.05 vs. BW373U86), suggesting an EGFR dependent mechanism. Surprisingly co-treatment with GM6001 did not significantly influence δ-OR mediated Erk1/2 activity. Akt phosphorylation was increased by more than 60% with BW373U86 (p≤0.05 vs. CTRL) and this response was abolished via treatment with the selective EGFR antagonist AG1478 or the selective MMP inhibitor GM6001. This provides further evidence that adenosinergic and opioidergic protective signalling during ischaemia-reperfusion requires the activity of
EGFRs and MMPs.
Conclusions: As a whole, the present study confirms an essential interaction between ARs and ORs in the heart, with kinase signalling and tissue protection via either A1ARs or -ORs exhibiting common and essential dependencies on activity of both receptors. The basis of this intriguing response remains unclear, although we show that both receptors engage distal kinases (and cardioprotection) in an MMP/EGFR dependent manner, adding an additional level to this novel cross-talk. This research provides further insight into cardioprotective receptor interactions in the heart, potentially leading to the development of new pharmacotherapeutics and improved outcomes for cardiovascular disease patients. Further research is needed to clarify the mechanism behind adenosinergic and opioidergic cross-talk and cardioprotection, potentially exploring membrane signalling, temporal expression of kinases, existence of A1AR/δ-OR dimers/oligomers, and concepts such as dual agonism and potential signalling thresholds for protection.Thesis (Masters)
Master of Medical Research (MMedRes)
School of Medical Science
Griffith Health
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Courneya, Carol Ann Margaret. "The relationship between sinoaortic baroreceptors, atrial receptors and the release of vasopressin in the anaesthetized rabbit." Thesis, University of British Columbia, 1987. http://hdl.handle.net/2429/26984.
Full textAbstract:
Vasopressin, a hormone released from the neurohypophysis, contributes to the regulation of body fluid balance through its known actions on the kidney and the vasculature. Release of vasopressin is influenced by plasma osmolality and by afferent activity from sensory receptors in the high and low pressure vascular systems. Previous studies have not defined the relative importance of the carotid sinus baroreceptors, aortic baroreceptors and atrial receptors in the control of the plasma concentration of vasopressin in the rabbit.
Experiments were carried out in anaesthetized rabbits to define the quantitative relationship between stimulation of the carotid sinus baroreceptors and the plasma concentration of vasopressin. This relationship was examined in the presence and absence of afferent input from the aortic and atrial receptors. Changes in blood volume were induced to produce a change in the stimulus to the aortic baroreceptors and atrial receptors at high or low, constant carotid sinus pressure. Section, of the aortic depressor nerves and the vagus nerves allowed examination of the individual contributions of atrial receptors or aortic baroreceptors on the plasma concentration of vasopressin. It was also possible to examine the interaction between the carotid sinus baroreceptors and the aortic and atrial receptors.
The results showed that plasma concentration of vasopressin was reduced by minimal stimulation of carotid sinus baroreceptors and that maximal inhibition of the release of vasopressin was achieved with a relatively low total arterial baroreceptor input. No influence of carotid sinus baroreceptors on vasopressin release was seen in the presence of intact aortic baroreceptors demonstrating the important interaction between the effects of stimulation of these two sets of receptors. It was not possible to demonstrate, in the rabbits used in this study, a significant contribution of atrial receptors to the control of vasopressin release either in response to changes in carotid sinus pressure or in response to changes in blood volume. To minimize the inhibitory effect of arterial baroreceptors on the release of vasopressin the aortic depressor nerves were cut and carotid sinus pressure was set at a low level. It was still not possible to demonstrate an effect of a reduction in blood volume on vasopressin release, confirming the absence of a contribution from atrial receptors in the anaesthetized rabbit.
There appears to be considerable variation between species in the contribution of the different receptor groups to the release of vasopressin. The results suggest that in the normal rabbit there is likely to be significant tonic inhibition of the release of vasopressin by stimuli arising from arterial baroreceptors. The absence of a demonstrable influence of atrial receptors in these rabbits is consistent with findings in primates but differs from those in dogs. It is unlikely that changes in plasma vasopressin concentration induced by small changes in blood volume contribute to the control of arterial pressure through direct effects on vascular resistance and capacitance.Medicine, Faculty of
Cellular and Physiological Sciences, Department of
Graduate
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Janota, Danielle Marie. "Alpha1-Adrenergic Receptor Activation Mimics Ischemic Postconditioning in Cardiac Myocytes." Kent State University / OhioLINK, 2014. http://rave.ohiolink.edu/etdc/view?acc_num=kent1406562863.
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Saxena, Ankur. "Cell migration and survival pathways in cardiac development and disease." Access to abstract only; dissertation is embargoed until after 12/20/2006, 2005. http://www4.utsouthwestern.edu/library/ETD/etdDetails.cfm?etdID=138.
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Zhang, Yanhui. "A comparative study of the individual and combined electrophysiological effects of mutations in the cardiac sodium channel and ryanodine receptor." Thesis, University of Cambridge, 2011. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.609704.
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Qing, Feng. "Studies of beta-adrenergic receptors in vivo in humans using the CGP-12177 ligand and positron emission tomography." Thesis, Imperial College London, 1999. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.325236.
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Dando, Simon Burke. "The role of 5-HT receptors in the modulation of the reflex activation of cardiac vagal motoneurones." Thesis, University College London (University of London), 1995. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.309288.
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Alhajoj, Ahmad Mohammed. "INACTIVATION OF AT1a RECEPTORS ATTENUATE LACTATE ACCUMULATION AND IMPROVE CARDIAC PERFORMANCE AND ACID-BASE HOMEOSTASIS DURING ENDURANCE EXERCISE." Wright State University / OhioLINK, 2014. http://rave.ohiolink.edu/etdc/view?acc_num=wright1396018497.
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McCabe, Christopher. "The effects of drugs acting at endothelin receptors on the cardiac electrophysiology of normal and ischaemic rabbit hearts." Thesis, University of Strathclyde, 2004. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.401508.
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Maan, Gagandeep. "Signal transduction mechanisms for lysophosphatidic acid mediated cardiac differentiation of P19 stem cells." Thesis, University of Hertfordshire, 2018. https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.768493.
Full textAbstract:
The role of endogenous molecules in facilitating stem cell differentiation into cardiomyocytes is yet to be fully understood. SPC and S1P, common biolipids, promote cardiac differentiation of mesenchymal stem cells and cardiac progenitor cells, however, the same potential of closely related lysophosphatidic acid (LPA) has only recently become evident. The initial cardio-protection offered by elevated LPA levels in response to acute myocardial infarction and the ability of this biolipid to mediate other cellular fates served as a rationale to investigate the ability of LPA to mediate the cardiac differentiation of the murine P19 teratocarcinoma cell line and further examine the role of signalling molecules critical to lineage commitment. All experiments were carried out using P19 stem cells, cultured in supplemented alpha-minimal essential medium. Cells were aggregated into embryoid bodies in the presence of 5µM LPA in non-tissue grade Petri dishes over the course of 4 days to commence the differentiation process. Inhibitors were added 60 minutes before LPA while control cells were cultured in medium only. Embryoid bodies were transferred to 6-well tissue culture grade plates and cultured for a further 6 days. Cardiac differentiation was assessed by examining the expression of ventricular myosin light chain (MLC1v) by western blot and the role of LPA receptors 1-4, PKC, PI3K, MAPKs, and NF-κB were determined by examining the changes in this expression in the presence of selective inhibitors. The induction and regulation of GATA4, MEF2C, ATF2, JNK, and YAP was also determined by western blotting. The activity and regulation of transcription factors, AP-1 and NF-κB, and the MAPKs was determined using ELISA kits. LPA induced the differentiation of P19 cells into cardiomyocytes most effectively when used at a concentration of 5µM as evidenced by the expression of MLC1v on day 10 of the differentiation process. Inhibition of LPA receptor 4 (0.1mg/mL Suramin), LPA receptors 1/3 (20µM Ki16425), LPA receptor 2 (7.5nM H2L5186303), PKC (10µM BIM1), PI3K (20µM LY294002), ERK (20µM PD98059), JNK (10µM SP600125), and NFκB (0.01nM CAY10470) blocked LPA induced expression of MLC1v. GATA4, MEF2C, pcJun, pJunD, and pATF2 expression increased in a time-dependent manner peaking at day 10 in LPA treated cells. GATA4 and pcJun expression was suppressed by all the inhibitors whereas MEF2C expression was unaffected by CAY10470, pJunD expression was unaffected by H2L5186303, pATF2 and NF-κB expression was unaffected by LY294002, but the latter was enhanced by Suramin. JNK was transiently phosphorylated in all cells whereas YAP was dephosphorylated 24-48 hours after EB formation in LPA treated cells and were both affected by Ki16425 and partially by H2L5186303 treatment. In conclusion, the studies carried out in this thesis have shown that LPA mediates the cardiac differentiation of P19 cells through LPA receptor 2, partially through receptors 1/3, and possibly through receptor 4. Conceivably downstream of these receptors, PKC, PI3K, MAPK, and NF-κB signalling pathways converge on the regulation of cardiac-specific transcription factors GATA4 and MEF2C along with ubiquitous transcription factor AP-1. JNK signalling is initiated through LPA receptors 1/3 and partially through receptor 2 to commence the cardiac program however the role of JNK and YAP in the proliferation of aggregating EBs is yet to be entirely established.
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Owen, Laura Jean. "Calcium and Redox Control of the Calcium Release Mechanism of Skeletal and Cardiac Muscle Sarcoplasmic Reticulum." PDXScholar, 2011. https://pdxscholar.library.pdx.edu/open_access_etds/430.
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The sarcoplasmic reticulum is an internal membrane system that controls the Ca²⁺ concentration inside muscle cells, and hence the contractile state of both skeletal and cardiac muscle. A key protein that that regulates the Ca²⁺ concentration in this membrane is known as the calcium release channel (CRC). The effects on Ca²⁺ dependent activation is of major importance in the study of CRC since other channel modifiers cannot effect the channel in the absence of Ca²⁺, or they require Ca²⁺ for maximum results. In this study of the high-affinity Ca²⁺ binding site, expected increases in total binding and shifts in the sensitivity of the channel to Ca²⁺ were observed when the pH increased or the solution redox status became more oxidative. Ranolazine, a drug used for treating Angina Pectoris (chest pain), desensitized the cardiac CRC activation but had no effect on the skeletal CRC. This selective desensitization may be the cause of Ranolazine's beneficial therapeutic effects. Both Ranolazine, and homocystein thiolactone (HCTL), a naturally occurring derivative of homocysteine, alters Ca²⁺ dependent activation by calcium without changing the number of channels found in the open state. Surprisingly the effect of HCTL was observed only in a reduced redox potential which leads to speculation that the formation of an alpha-carbon radical by HCTL on the cardiac CRC only occurs if select thiols are in a reduced state.
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Hamilton, Shanna. "Functional heterogeneity of CPVT-mutant human cardiac ryanodine receptors : evaluation of the influence of S2031 and S2808 phosphorylation sites." Thesis, Cardiff University, 2017. http://orca.cf.ac.uk/111392/.
Full textAbstract:
Human cardiac ryanodine receptors (hRyR2) are calcium (Ca2+) release channels central to excitation-contraction coupling. Mutations in hRyR2 are linked to catecholaminergic polymorphic ventricular tachycardia (CPVT), a genetic disorder characterized by arrhythmia, occurring under adrenergic drive. Recent studies suggest gain-of-function mutant channels may undergo different mechanisms of dysfunction, with some showing altered Ca2+ release under basal conditions and others requiring an additional trigger (possibly in the form of β-adrenergic phosphorylation). This study evaluated whether mutants from different domains of hRyR2 (S2246L and N4104K) were functionally heterogeneous in a cellular setting and whether this was related to phosphorylation status. Cells (human embryonic kidney 293) expressing N4104K-hRyR2 displayed smaller, faster Ca2+ release events than those expressing the wild type (WT), while those of cells expressing S2246L-hRyR2 were similar to WT. However, a lower proportion of S2246L cells showed any kind of Ca2+ release functionality compared to those expressing WT or N4104K, reinforcing that these mutations cause different types of dysfunction. Assessment of phosphorylation status using site-specific antibodies for protein kinase A (PKA) target sites S2808 and S2031 showed that mutant phosphorylation levels were different to each other and to that of the WT, indicating a possible role of phosphorylation in this. Activation of PKA-mediated phosphorylation in cells using a cyclic AMP analogue resulted in changes to the kinetics of spontaneous Ca2+ release via WT hRyR2, but did not significantly affect that of mutants. Genetic phosphorylation at either PKA site (S2808D and S2031D) altered the Ca2+ release of mutants as well as WT hRyR2, but this was found to be due to changes in expression of sarco-endoplasmic reticulum Ca2+-ATPase (SERCa) pump, which also contributes to Ca2+ homeostasis. These findings reinforce the concept that phosphorylation is linked to dysfunction and contributes to our understanding of hRyR2 mutation in arrhythmia, highlighting that ‘gain-of-function’ does not necessarily equate to dysfunction via the same mechanism.
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Lang-Lemckert, Julian Charles. "An evaluation of Glucocorticoid Receptors in A549 cells and cardiac fibroblasts: Potential in vitro models of COPD and Heart Failure." Thesis, Griffith University, 2018. http://hdl.handle.net/10072/382691.
Full textAbstract:
Introduction
Chronic Obstructive Pulmonary Disease (COPD) and Heart Failure (HF) are two diseases that contribute significantly to disease morbidity and mortality within Australia. Both conditions exhibit excessive inflammation of the pulmonary tissue and cardiac tissue respectively which plays a significant role in disease onset and progression. Recent clinical and in vitro studies have begun to focus upon glucocorticoid receptor (GR) function associated with these conditions, as the GRs produce anti-inflammatory responses when activated. Studies using pulmonary and cardiac cells, in vitro, have observed that decreases within GR signalling (i.e. GR resistance) may accelerate the progression of the disease and worsen prognosis. Additionally, recent studies have also shown that the administration of mineralocorticoid receptor (MR) antagonists to cardiac and pulmonary cells are capable of reducing inflammation. Therefore understanding the changes occurring in GR and MR populations associated with COPD and HF may provide further insight into the inflammatory pathways underlying these diseases; therefore allowing for the development of more effective treatments for both conditions.
Experimental Aims
The aim of this study was to investigate the effect of 24 hours incubation with the GR agonist dexamethasone in both adenocarcinoma cell lines (A549 cells) and primary Human Cardiac Fibroblasts (HCF), in order to identify whether GR resistance could be induced in these cells lines (simulating the decreased GR signalling noted within COPD and HF patients). Following treatment, Western blotting analysis of GR and MR populations, as well as fluorescent proliferation assays were utilized to determine if GR resistance could be accurately measured within these cells.
Methods
The cellular viability (as measured via MTT and LDH assays) of A549 and HCF cells in response to 24 hours treatment with concentrations of the GR agonist dexamethasone in the presence or absence of the GR inhibitor mifepristone (and vehicle controls) was measured in order to determine optimum concentrations of these drugs for the 24 hour study period. Following viability studies, cells were then exposed to dexamethasone (100nM) and/or mifepristone (10nM) for 24 hours. The A549 and HCF cell proliferation rates were then measured using the fluorescence-based 2-deoxybromouridine (BRDU) proliferation assay to determine if any changes in dexamethasone responsiveness (as measured via a ratio between dexamethasone : vehicle control absorbance) could be detected. Further, A549 and HCF cells were then treated for 24 hours with dexamethasone (100nM) in the presence or absence of mifepristone (10nM) then lysed with 2X RIPA lysis buffer supplemented with protease and phosphatase inhibitors in order to form protein lysates for Western blotting. Western blotting analysis was then conducted in order to determine the expression of the three GR gene variants GRα-A, GRβ and GRγ, as well as MR. All Western blots were normalized to both an internal standard and housekeeping protein (cofilin). All data was presented as mean ± SEM and one-way ANOVA performed using GraphPad Prism, with a p value of 0.05 utilized to register statistical significance.
Results
MTT and LDH cellular viability assays confirmed that dexamethasone (100nM) and mifepristone (10nM) did not have any significant impact upon the cellular viability of A549 and HCF cells over a 24 hour period (p>0.05). Subsequent BRDU proliferation assays on A549 cells revealed only a significant difference in cell proliferation rates between the dexamethasone (100nM) only treated and the combined dexamethasone (100nM) and mifepristone (10nM) treatment groups (p<0.05). These results were not repeated in the HCF cell experiments, which showed no significant difference in proliferation rates between any of the treatment groups (p>0.05). Subsequent protein analysis via Western blotting revealed that all treatments significantly reduced the protein expression of GRα-A within A549 cells relative to control (p<0.05). In contrast, protein analysis of HCF cells revealed only a significant decrease in GRα-A protein expression in HCF cells treated with dexamethasone (100nM, p<0.01). GRβ and GRγ protein expression was found to be significantly decreased in A549 cells treated with the combined treatment of dexamethasone (100nM) and mifepristone (10nM) only when compared to protein levels in untreated cells (p<0.05). Alternatively, GRγ protein expression did not differ significantly differ between HCF treatment groups (p>0.05) and GRβ protein was not expressed within measurable concentrations within any of the HCF treatment groups. Finally, both A549 and HCF cells did not express MR within measurable quantities.
Conclusion
This research is the first project to investigate the effects of dexamethasone treatment on both the development of GR resistance (as measured via BRDU fluorescence assays) and GR and MR protein expression in both A549 and HCF cells. Novel findings include the BRDU analysis within A549 cells, which indicated the method was capable of detecting some changes in proliferation rates which correlated well with changes within GRβ and GRγ protein expression changes measured using Western blot procedures. This method was also found to be ineffective in measuring GR resistance within HCF cells, as the decrease in GRα-A protein expression observed in the Western blots produced no change in BRDU cell proliferation results. Overall, further studies should be conducted into developing the BRDU method as a measurement of GR resistance for use in primary cells, in vitro. Due to the inconsistencies noted between the findings this study and those presented in literature, further investigations on the impact of dexamethasone and mifepristone on GR regulation in A549 and HCF cells should be conducted.Thesis (Masters)
Master of Medical Research (MMedRes)
School of Medical Science
Griffith Health
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Smith, Frank Melvin. "Arterial baroreceptor control of the circulation during forced dives in ducks (Anas Platyrhynchos var.)." Thesis, University of British Columbia, 1987. http://hdl.handle.net/2429/27533.
Full textAbstract:
When dabbling ducks are involuntarily submerged, arterial vasoconstriction produces a large increase in the peripheral resistance to blood flow which is balanced by a decrease in output of the heart, and arterial blood pressure is maintained. Arterial baroreceptors sense systemic blood pressure, and provide the afferent information to the baroreflex for pressure regulation. The effector limbs of the baroreflex are the same as those involved in the diving responses, and the baroreceptors are likely to be important in the integration of the cardiovascular responses to diving. The purpose of this study was to investigate the role of the arterial baroreceptors in maintaining blood pressure during diving, and in the initiation and maintenance of the diving responses.
Baroreceptor function was studied by diving ducks at various times after barodenervation, and by electrically stimulating the central end of one baroreceptor nerve in baroreceptor-denervated animals to simulate a controlled baroreceptor input before and during submersion.
Intact baroreceptor innervation was not necessary for the development of peripheral vasoconstriction, but loss of the baroreceptors modified the cardiac response to submersion by impairing the vagally mediated bradycardia. There was no effect of baroreceptor nerve stimulation on peripheral
resistance during diving, and the baroreflex operated via the heart rate in modulating blood pressure early in the dive. Later in the dive, stimulation was ineffective in altering either heart rate or blood pressue. Strong chemoreceptor drive results from decreased blood oxygen and increased carbon dioxide levels in the dive, and the results of experiments to determine the mechanism of baroreflex attenuation showed that an interaction between chemoreceptor and baroreceptor inputs may be at least partly responsible for reducing baroreflex effectiveness.
The main conclusion from this work is that the arterial baroreceptors contribute to the diving responses through modulation of heart rate, to help balance the fall in cardiac output against the baroreceptor-independent peripheral vasoconstriction in the first minute of forced dives.Science, Faculty of
Zoology, Department of
Graduate
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Majeed, Zana R. "MODULATORY ACTIONS OF SEROTONERGIC SYSTEM IN CARDIAC FUNCTION, BEHAVIOR, AND SENSORIMOTOR CIRCUIT ACTIVITY IN DROSOPHILA MELANOGASTER." UKnowledge, 2016. http://uknowledge.uky.edu/biology_etds/32.
Full textAbstract:
In this dissertation, I have focused on the role of serotonin (5-HT) as a modulator in heart rate, feeding and locomotion behaviors as well as sensorimotor circuit activity in Drosophila melanogaster. A general overview in the actions of the serotonergic (5-HTergic) system on the larval heart and nervous system in larvae and adults is reviewed in Chapter One. I sought to further study the actions of serotonergic system to provide additional insights into cellular and molecular underpinnings in the actions of 5-HT.In Chapter two, I present studies on mechanisms of action by 5-HT in larvae cardiac system. For this purpose, genetic and pharmacological approaches were used. The transgenic flies used expressed hM4Di receptors (designer receptors exclusively activated by designer drugs (DREADDs)) which were employed to manipulate the activity of Gαi heterotrimeric protein through activation of engineered G-protein coupled receptors hM4Di DREADD. The activation of hM4Di DREADD receptors by clozapine-N-oxide (CNO) arrested the heart beat; however, pharmacological manipulation of adenylyl cyclase activity and cAMP levels had no significant effect on heart rate. In Chapter Three the role of various 5-HT receptor subtypes that mediate 5-HT action in larval cardiac tissue is addressed. In this study, various 5-HT agonists and antagonists were employed. The pharmacological results demonstrate that a 5-HT2 agonist significantly increases the heart rate. Furthermore, 5-HT2 antagonist, markedly reduces the effect of 5-HT. In addition, I employed genetic approaches to corroborate the pharmacological results.
In addition, I investigated the role of the 5-HTergic system in locomotion and feeding behaviors as well as in modulation of sensorimotor circuits. This study is delineated in Chapter Four. The 5-HT biosynthesis was dysregulated by feeding Drosophila larvae various pharmacological agents. 5-HT receptor subtypes were manipulated using RNA interference mediated knockdown and 5-HT receptor insertional mutations. Moreover, synaptic transmission at 5-HT neurons was blocked or induced in both larvae and adult flies. The results demonstrate that disruption of components within the 5-HT system significantly impairs locomotor activity and feeding behavior in larvae. In addition, acute activation of 5-HT neurons disrupts normal locomotor activity in adult flies. In Chapter Five, I addressed direct actions of fluoxetine on synaptic transmission at neuromuscular junctions (NMJs), neural properties, and cardiac function unrelated to fluoxetine’s action as a selective 5-HT reuptake inhibitor using Drosophila, crayfish and primary neurons in mouse model system. Fluoxetine application blocked action potentials in crayfish axons, enhanced occurrences of spontaneous synaptic vesicle fusion events at NMJs of both Drosophila and crayfish. In rodent primary neurons, fluoxetine application resulted in increase of cytoplasmic Ca2+.
I also developed teaching modules, which are presented in Chapter Seven, to guide students how to exploit a vast array of genetic tools, such as optogenetics in Drosophila to manipulate various neural circuits and to observe their effects on behavior and sensorimotor circuit activity. I also developed a module to teach college level students a hands-on experiment regarding proprioception and tension receptors in crab limb, which is detailed in Chapter Eight.
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Talasila, Amarnath. "Characterisation of P2Y receptors expressed in neonatal rat cardiac fibroblasts and their role in a model of ischaemic heart disease." Thesis, Nottingham Trent University, 2007. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.443325.
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Chen, Chen. "Evaluation of the coxsackievirus and adenovirus receptor (CAR) as a therapeutic target in cardiac disease." Doctoral thesis, Humboldt-Universität zu Berlin, Mathematisch-Naturwissenschaftliche Fakultät I, 2009. http://dx.doi.org/10.18452/15980.
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Der Coxsackievirus- und Adenovirusrezeptor (CAR) ist ein Typ I Transmembran-protein, das an der Adsorption von Viren und der Aufrechterhaltung von Zell-Zellkontakten beteiligt ist. Coxsackievirus B3 (CVB3) Infektionen sind eine häufige Ursache für akute Myokarditis, die bei Patienten häufig zu chronischer Kardiomyopathie bis zur Herzinsuffizienz führen können. CAR ist für die Aufnahme von Viren in unterschiedliche Zelltypen verantwortlich und damit ein potentielles Ziel bei der Therapie und Prävention von CVB3-Infektionen. Der komplette Knockout von CAR ist embryonal letal. Die betroffenen Embryonen zeigten Missbildungen des Herzens. Weiterhin konnte eine reduzierte Expression von Connexinen im Knockout beobachtet werden – ein mögliches Zeichen gestörter interzellulärer Kommunikation. In konditionellen CAR Knockout Tieren führte die Infektion mit CVB3 im Gegensatz zu CVB3-infizierten Wildtyp Kontrolltieren zu keinen pathologischen Veränderungen oder eine Erhöhung von Entzündungsmarkern. Die kontraktile Funktion des CVB3-infizierten Knockout Herzen war erhalten. Um mögliche unerwünschte Konsequenzen aus dem Verlust von CAR zu untersuchen, wurde eine umfassende kardiale Phänotypisierung durchgeführt, die AV-block im Knockout-Herzen zeigte. Der zugrunde liegende Mechanismus betrifft die Interaktion von Tight- und Gap-Junctions mit veränderter Expression und Lokalisierung von Connexinen, sowie die interzelluläre Kommunikation zwischen CAR-Knockout Kardiomyzeten. CAR ist essentiell für eine normale Embryonalentwicklung und kardiale Funktion. Das CAR-Knockout-Modell bietet einerseits den ersten genetischen Hinweis für eine Rolle von CAR als Virusrezeptor in vivo und belegt andererseits die Relevanz von direkter Virus-vermittelter Symptomatik gegenüber einer sekundären autoimmun- Komponente in CVB3-induzierten Herzerkrankungen. Damit ist CAR ein potentielles therapeutisches Target in der Prävention und Behandlung von viraler Myokarditis.The coxsackievirus and adenovirus receptor (CAR) is a type I transmembrane protein involved in virus uptake and the maintenance of cell-cell contacts. Coxsackievirus B3 (CVB3) infections are frequent causes of human acute myocarditis, often resulting in chronic cardiomyopathy that may progress into terminal heart failure. The coxsackievirus and adenovirus receptor (CAR) is involved in virus uptake into various cell types and has therefore been suggested as a therapeutic target to prevent or treat CVB3 induced diseases. The complete CAR-knockout was embryonic lethal at midgestation with cardiac malformation. Connexin expression was decreased in the knockout, suggesting an abnormal cell-cell communication secondary to the loss of CAR. The role of CAR in murine viral myocarditis was investigated using the inducible CAR-knockout infected with CVB3. Unlike control animals exposed to CVB3, the cardiac inducible knockout mice did not exhibit structural changes such following CVB3 infection, or increased production of markers of inflammation, and severe contractile dysfunction. To evaluate possible adverse effects that might result from CAR deficiency, we implemented a detailed cardiac phenotyping protocol and found that CAR deficient animals developed AV nodal block. The underlying mechanism relates to the crosstalk of tight and gap junctions with altered expression and localization of connexins that affect the communication between CAR knockout cardiomyocytes. Thus, CAR is essential for embryonic development and normal cardiac function. The CAR-knockout does not only provide the first genetic evidence to establish CAR as the CVB3 receptor in vivo, but furthermore demonstrates the relevance of direct virus-mediated pathology versus a secondary autoimmune component in CVB3 induced heart disease. Our data suggest that CAR is a suitable target to help prevent and treat viral myocarditis.
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Diniz, Gabriela Placoná. "Avaliação da contribuição do receptor AT1 de angiotensina II e do papel da via de sinalização AKT/GSK-3/mTOR no processo de hipertrofia do cardiomiócito induzido pelo hormônio tiroideano." Universidade de São Paulo, 2010. http://www.teses.usp.br/teses/disponiveis/42/42131/tde-25032010-143422/.
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O presente estudo avaliou o papel do receptor AT1 de Angiotensina II no desenvolvimento da hipertrofia dos cardiomiócitos promovida pelo T3, bem como a participação dos mecanismos intracelulares deflagrados pelo receptor AT1 neste modelo de hipertrofia cardíaca. O silenciamento do receptor AT1 com RNA de interferência preveniu totalmente o desenvolvimento da hipertrofia dos cardiomiócitos induzida pelo T3. Os cardiomiócitos tratados com T3 demonstraram uma rápida ativação da via da Akt/GSK-3/mTOR, a qual foi atenuada ou prevenida pelo silenciamento do receptor AT1. Ainda, a expressão de Angiotensina I/II no lisado celular e a expressão do receptor AT1 foram rapidamente aumentados pelo T3. Esses dados demonstram pela primeira vez que o receptor AT1 é um mediador crítico da hipertrofia dos cardiomiócitos induzida pelo T3, bem como para a ativação da via da Akt, sugerindo que a via Ang I/II-AT1-Akt/GSK-3/mTOR corresponde a um potencial mediador dos efeitos tróficos exercidos pelo T3 nessas células.The present study investigated the role of Angiotensin type 1 receptor (AT1R) in T3-induced cardiomyocyte hypertrophy, as well as the participation of the intracellular mechanisms mediated by AT1R in this cardiac hypertrophy model. The AT1R silencing using small interfering RNA totally prevented the development of T3-induced cardiomyocyte hypertrophy. The cardiomyocytes treated with T3 demonstrated a rapid activation of Akt/GSK-3/mTOR signaling pathway, which was attenuated or prevented by the AT1R silencing. In addition, local Angiotensin I/II (Ang I/II) levels and the AT1R expression were rapidly increased by T3 treatment. These data demonstrate for the first time that the AT1R is a critical mediator to the T3-induced cardiomyocyte hypertrophy, as well as to the activation of the Akt signaling, suggesting that the Ang I/II-AT1R-Akt/GSK-3/mTOR pathway corresponds to a potential mediator of the trophic effect exerted by T3 in cardiomyocytes.
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Konrad, David. "Cardiac function in experimental septic and non-septic conditions with special reference to the endothelin system /." Stockholm, 2006. http://diss.kib.ki.se/2006/91-7140-984-X/.
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Abrahão, Mariana Vieira. "Papel do Sistema Renina-Angiotensina (SRA) na hipertrofia cardíaca induzida por lesão renal isquêmica." reponame:Repositório Institucional da UFABC, 2015.
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Orientadora: Profa. Dra.Marcela Sorelli Carneiro RamosTese (doutorado) - Universidade Federal do ABC, Programa de Pós-Graduação em Biossistemas, 2015.
Recentemente, dados na literatura demonstram a estreita interacao patofisiologica existente entre os rins e o coracao. Conhecida como sindrome cardio-renal, essa patologia e capaz de promover hipertrofia e falencia cardiaca a partir de um quadro de lesao renal. Sabe-se que a lesao renal isquemica (LRI) promove a liberacao de diferentes citocinas inflamatorias que tem o coracao como tecido alvo e sao capazes de promover a instalacao do quadro hipertrofico, agindo, por exemplo, por meio de receptores semelhantes ao Toll (toll-like receptors - TLR). Alem de mediadores inflamatorios, trabalhos presentes na literatura ja comprovaram a direta relacao entre alteracoes no sistema renina-angiotensina (SRA) e nos niveis de Angiotensina II (Ang II) com o aumento da massa cardiaca. O presente estudo objetivou investigar o papel do SRA com a hipertrofia cardiaca (HC) induzida por um modelo experimental de LRI em camundongos tratados ou nao com bloqueadores do SRA, Losartan (Los) e Enalapril (Ena). O quadro de LRI foi induzido cirurgicamente atraves da oclusao do pediculo renal esquerdo por 60 minutos seguido de reperfusao. Apos 12, 15 ou 20 dias os tecidos foram removidos para a realizacao de analises macromorfometricas, moleculares e funcionais. Os principais resultados indicam que a cirurgia de isquemia renal e reperfusao foi capaz de gerar um quadro de falencia renal e induzir HC de maneira independente de aumento na pressao arterial. Ainda, no periodo analisado, observou-se aumento nos niveis sericos de TNF-¿¿ e Ang II, elevados niveis de expressao genica ou proteica de AT1, ECA-2, TLR-2, TLR-4 e NFk¿À, sugerindo relacao desses componentes com a HC. Os tratamentos com Los e Ena reverteram completamente a HC observada e aboliram o aumento na expressao cardiaca de TLRs, AT1R e ECA-2 e modularam diferencialmente os niveis sericos de Ang II e citocinas inflamatorias. Juntos, os dados sugerem um papel crucial do SRA na regulacao do quadro patologico neste modelo, atuando juntamente com o sistema imune inato na regulacao da patogenese da HC atraves da modulacao de seus principais componentes.
Recently published data demonstrate the close pathophysiological interaction between the kidneys and the heart. Known as cardio-renal syndrome, this pathology is capable of promoting hypertrophy and heart failure starting from renal injury. It is known that ischemic renal injury (IRI) promotes the release of various inflammatory cytokines that have the heart as a target tissue and are capable of promoting hypertrophy acting through the Toll-like receptors (TLR). In addition to inflammatory mediators, literature has extensively demonstrated the direct correlation between changes in the renin-angiotensin system (RAS) and the levels of angiotensin II (Ang II) within the increase in cardiac mass. This study aimed to investigate the role of the RAS with cardiac hypertrophy (CH) induced by an experimental model of IRI in mice treated or not with RAS blockers, Losartan (Los) and Enalapril (Ena). The IRI was surgically induced by occlusion of the left renal pedicle for 60 minutes followed by reperfusion. After 12, 15 or 20 days, tissues were removed and morphological, molecular, and functional analysis were performed. The leading results indicate that renal ischemia and reperfusion surgery was capable of generating renal failure which subsequently induced HC in a blood-pressure independent manner. Also, over this period, there was an increase in serum levels of TNF-á and Ang II, high levels of gene or protein expression of AT1, ACE-2, TLR-2, TLR-4 and NFkâ, suggesting a cross-talk within these components and CH development. Treatment with Los or Ena has completely reversed the CH and abolished the increase observed in cardiac expression of TLRs, NFkâ, ACE-2 and AT1R, and also differentially modulated Ang II and inflammatory cytokines serum levels. Together, the data suggest a critical role for RAS in the regulation of the pathological condition in this model, acting together with the innate immune system in the pathogenesis of CH through modulation of its main components.
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Wang, Xiaohui. "Role of TLRs, Hippo-YAP1 Signaling, and microRNAs in Cardiac Repair and Regeneration of Damaged myocardium During Ischemic Injury." Digital Commons @ East Tennessee State University, 2017. https://dc.etsu.edu/etd/3287.
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Cardiovascular disease is a leading cause of death in the United States. Toll-like receptor (TLR)-mediated pathways have been demonstrated to play a role in myocardial ischemia/reperfusion (I/R) injury. We and others have shown that PI3K/Akt signaling is involved in regulating cellular survival and protecting the myocardium from I/R induced injury. In this dissertation, we provide compelling evidence that miR-125b serves to “fine tune” TLR mediated NF-kB responses by repressing TNF-a and TRAF6 expression. We constructed lentiviral expressing miR-125b, delivered it into the myocardium. The data showed that delivery of lentivirus expressing miR-125b significantly reduces myocardial infarct size and improves cardiac function in I/R hearts. Mechanistic studies demonstrated that miR-125b negatively regulates TLR mediated NF-kB activation pathway by repressing TNF-a and TRAF6 expression in the myocardium.
We also observed that transfection of the myocardium with lentivirus expressing miR-214 markedly attenuates I/R induced myocardial infarct size and cardiac dysfunction. We demonstrated that miR-214 activates PI3K/Akt signaling by targeting PTEN expression in the myocardium.
We also investigated the role of TLR3 in neonatal heart repair and regeneration following myocardial infarction (MI). Wild type (WT) neonatal mice showed fully cardiac functional recovery and small infarct size, while TLR3 deficient mice exhibited impaired cardiac functional recovery and large infarct area after MI. Poly (I:C), a TLR3 ligand, administration significantly enhances glycolysis, YAP1 activation and the proliferation of WT neonatal cardiomyocytes. 2-deoxyglucose (2-DG), a glycolysis inhibitor treatment abolished cardiac functional recovery and YAP1 activation in neonatal mice after MI. In vitro either inhibition of glycolysis by 2-DG or inhibition of YAP1 activation prevents Poly (I:C) induced YAP1 activation and neonatal cardiomyocyte proliferation. Importantly, YAP1 activation increases miR-152 expression, leading to cardiomyocyte proliferation through suppression P27kip1 and DNMT1 expression.
We conclude that microRNAs play an important role in TLR modulation induced protection against myocardial I/R injury by increasing the activation of PI3K/Akt signaling pathway, decreasing TLR/NF-kB mediated inflammatory response, and suppressing activation of apoptotic signaling following myocardial I/R injury.
In addition, TLR3 is an essential for neonatal heart repair and regeneration after myocardial infarction. TLR3 modulation could be a novel strategy for heart regeneration and repair.
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Negri, Irene. "P2Y2 nucleotide receptor is a regulator of cardiac adipose tissue and its fat-associated lymphoid clusters at basal state and after myocardial infarction." Doctoral thesis, Universite Libre de Bruxelles, 2020. http://hdl.handle.net/2013/ULB-DIPOT:oai:dipot.ulb.ac.be:2013/312212.
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The research of new therapeutic strategies for cardiovascular diseases has seen in the last 15 years the introduction of a new participant: pericardial adipose tissue (PAT). This tissue is able to modulate cardiac function and its volume was sometimes linked to risk of cardiovascular diseases. Moreover, adipose-derived stem cells (ASCs) isolated from PAT are considered as the best suitable for new regenerative strategies aiming at healing ischemic myocardium. Although the interests in understanding the functions and the formation of pericardial adipose tissue are high, the current knowledge on this tissue is still scarce. In this work, the starting point was the consideration that nucleotide receptors are established regulators of many biological functions, including the differentiation of adult mesenchymal stem cells, immunity and inflammatory process. The P2Y4 receptor has been recently recognized as a negative regulator of cardiac fat formation and ASCs differentiation. The purpose of this thesis was to analyze the involvement of the nucleotide receptor P2Y2 in the formation of pericardial adipose tissue (PAT) and its ASCs differentiation. We also investigated the possible contribution of this receptor to the functions of recently discovered fat-associated lymphoid clusters (FALCs). Our study analyzed the PAT of mice deficient for P2Y2 at basal conditions and in a model of myocardial infarction. P2Y2-null mice showed a lower mass of PAT compared to WT, which was correlated with decreased adipogenic differentiation and maturation potential of pericardial ASCs in vitro. PAT of basal P2Y2-deficient mice displayed a reduced density of FALCs due to a reduced number of B cells. RNA-sequencing experiments identified many P2Y2 target genes in PAT linked to immunomodulation. We identified a polarization of FALCs macrophages towards anti-inflammatory M2c subtype in P2Y2-null mice. We correlated it with a decreased number of follicular helper T cells, known to contribute to B cell expansion in germinal centers. These data could be correlated with increased apoptosis of B lymphocytes. The data obtained using the mouse infarct model confirmed an expected enlargement of pericardial FALCs in ischemic conditions. P2Y2-null mice were characterized by a reduced expansion of B cells and myeloid cells migration in PAT. These results suggested a participation of P2Y2 receptor in regulating the post-MI inflammatory response by modulating the leukocytes populations in the pericardial adipose tissue’s lymphoid clusters. The effect of P2Y2 on PAT post-ischemic inflammatory state could contribute to the P2Y2-mediated cardioprotective effect of UTP described in previous literature. Our study defines P2Y2 nucleotide receptor as a regulator of the formation of pericardial fat and its inflammatory status in ischemic conditions. P2Y2 receptor could represent an interesting therapeutic target for the regulation of PAT functions before and after MI. In general, a better comprehension of PAT and its consideration in the post-ischemic regeneration process could lead to the development of new therapeutic strategies for treating cardiovascular diseases and the adjustment of existing therapies.Durant les 15 dernières années, un nouvel arrivant a fait son apparition dans la recherche de nouvelles approches thérapeutiques dans le domaine cardiovasculaire: le tissu adipeux cardiaque. Ce tissu est capable de moduler les fonctions cardiaques et son volume a pu être associé parfois à un risque de maladie cardiovasculaire. De plus, les cellules souches dérivées du tissu adipeux (ASCs) cardiaque sont considérées comme les mieux appropriées pour des stratégies thérapeutiques visant la réparation du myocarde ischémié. Bien que la compréhension de la fonction et de la formation du tissu adipeux cardiaque présente un intérêt majeur, la connaissance actuelle de ce tissu particulier est encore assez limitée. Pour le présent travail, le point de départ a été l’observation que les récepteurs nucléotidiques sont des régulateurs établis de nombreuses fonctions biologiques, incluant la différentiation des cellules souches mésenchymateuses et plus généralement la régulation de la réponse immune et inflammatoire. Le récepteur P2Y4 a été récemment reconnu comme un régulateur négatif de la formation du tissu adipeux cardiaque et de la différentiation des ASCs. Le but de cette thèse a été l’étude de l’implication du récepteur nucléotidiques P2Y2 dans la formation du tissu adipeux péricardique (TAP) et la différentiation des ASCs. Nous avons également investigué la contribution possible de ce récepteur dans la fonction des structures leucocytaires associées au tissu adipeux appelées FALCS pour fat-associated lymphoid clusters.Nous avons étudié le TAP de souris déficientes pour le récepteur P2Y2 à l’état de base et dans un modèle d’infarctus du myocarde. Les souris P2Y2 knock-out (KO) présentent une masse réduite du TAP corrélée avec le fait que l’absence du P2Y2 diminue la différentiation adipogénique et le potentiel de maturation des ASCs péricardiques in vitro. Le PAT des souris P2Y2 KO présentent une diminution de la densité de FALCs à l’état de base, principalement due à un nombre réduit de lymphocytes B, potentiellement corrélé à une apoptose accrue observée dans ces cellules. Nos expériences de RNA-sequencing ont identifié de nombreux gènes cibles du P2Y2 dans le PAT impliqués dans l’immunomodulation. Nous avons identifié une polarisation des macrophages de type M2c dans les FALCs de souris P2Y2 KO. Nous l’avons corrélée avec une diminution des lymphocytes T helper folliculaires connus pour contribuer à l’expansion des lymphocytes B dans les centres germinaux. Les données obtenues dans le modèle d’infarctus chez la souris ont confirmé une augmentation des FALCs péricardiques dans les conditions d’ischémie cardiaque. Les souris P2Y2 KO sont caractérisées par une expansion réduite des lymphocytes B et des cellules myéloïdes dans le TAP. Ces résultats suggèrent une participation du récepteur P2Y2 dans la régulation de la réponse inflammatoire post-infarctus par la modulation des populations leucocytaires dans les clusters lymphocytaires du tissu adipeux cardiaque. L’effet du P2Y2 sur l’état inflammatoire post-ischémique pourrait contribuer à l’effet cardioprotecteur de l’UTP médié par le P2Y2 et précédemment décrit dans la littérature.Notre étude définit le récepteur nucléotidique P2Y2 comme un régulateur de la formation du tissu adipeux péricardique et de son niveau inflammatoire dans des conditions ischémiques. Le récepteur P2Y2 pourrait représenter une cible thérapeutique intéressante pour la régulation des fonctions du PAT avant et après infarctus du myocarde. Plus généralement, une meilleure compréhension du tissu adipeux cardiaque et de son implication dans le processus de régénération cardiaque pourrait mener au développement de nouvelles stratégies thérapeutiques dans le traitement de maladies cardiovasculaires et à l’ajustement de thérapies déjà existantes.
Doctorat en Sciences biomédicales et pharmaceutiques (Médecine)
info:eu-repo/semantics/nonPublished