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|Title:||The role of hydrogen sulfide in normal and ischemic heart||Authors:||YONG QIAN CHEN||Keywords:||H2S, beta-adrenergic system, preconditioning, postconditioning, calcium, gasotransmitter||Issue Date:||29-Jul-2010||Citation:||YONG QIAN CHEN (2010-07-29). The role of hydrogen sulfide in normal and ischemic heart. ScholarBank@NUS Repository.||Abstract:||Ischemic heart disease is the leading cause of death in the western society and a major health problem in developing countries. In the current study, the role of hydrogen sulfide (H2S) in the cardioprotection against ischemic heart injury was investigated. Firstly, the role of H2S in excitation-contraction coupling in cardiomyocytes was studied. H2S was shown to negatively modulate the ?-adrenergic system, which is over-stimulated during ischemia/reperfusion, via inhibiting adenyly cyclase activity. This inhibition resulted in reduced cAMP production, and thus may prevent calcium overload-induced ventricular arrhythmias. Further experiments were conducted to confirm the cardioprotective effects of H2S in isolated rat heart and cardiomyocytes. Endogenous H2S production in heart was found to be suppressed in cardiomyocytes subjected to ischemia. Preconditioning or postconditioning the hearts with several episodes of brief ischemia significantly restored the H2S production in the heart accompanied by improved heart contractile function during reperfusion. Inhibition of H2S synthesis partially blocked the cardioprotective effect of both pre- and post-conditioning, indicating that endogenous H2S may, at least in part, mediate the protection given rise by these two maneuvers. The present study also demonstrated that NaHS, an H2S donor, was an effective pharmacological pre- and post-conditioning agent to ameliorate the cardiac injury induced by ischemia/reperfusion (I/R) in terms of cells death, cell morphology, intracellular calcium handling, cellular and heart contractile function, infarction size, and arrhythmias. The interaction between H2S and nitric oxide (NO), two important gasotransmitters, was also studied in this thesis. Mixture of NaHS with different NO donors and L-arginine, a main substrate for NO synthase to generate NO, exerted completely opposite effects on myocytes contractile function and calcium cycling, suggesting that a novel reaction product of H2S +NO, may be formed. Additional experiments demonstrated that this novel compound may be nitroxyl since this novel substance possesses several properties very similar to that of nitroxyl, like producing positive inotropic effect via cAMP/PKA, cGMP/PKG independent pathways, in which their effects were sensitive to thiols. In conclusion, H2S may negatively modulate the ?-adrenergic system which translates H2S into a good cardioprotective agent to protect the heart from ischemia/reperfusion injury, when the ?-adrenergic receptor is over-stimulated. In addition, the present study also demonstrated that H2S may sophisticatedly regulate excitation-contraction coupling in the heart by modulating intracellular calcium in a totally different manner in the presence of NO, suggesting the formation of a novel compound, which potentially plays a significant role during certain conditions like inflammation, when both gasotransmitters are highly produced.||URI:||http://scholarbank.nus.edu.sg/handle/10635/25050|
|Appears in Collections:||Ph.D Theses (Open)|
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