| Acute coronary artery diseases are the leading cause of mortality and morbidity in western countries. Cardiological practice has changed rapidly over the last few years, progressing from thrombolysis to direct coronary intervention and stenting to rapidly restore myocardial blood flow. Cardiac reperfusion after an acute myocardial infarction(MI) contributes to myocyte damage, generating what is referred to as myocardial ischemia/reperfusion injury(MIRI). Myocardial ischemia/reperfusion(I/R) injury may occur in many clinical pathological processes including thrombolysis of coronary artery thrombosis, heart transplantation, hypovolemic shock and severe infections, et al.Recent studies indicated that MIRI is related to oxidative stress leading to the imbalance between oxidative stress detrimental cascades for superoxide anion explosion which further reacts with lipid, protein and DNA, resulting damage to heart. Cardiomyocytes apoptosis occurs at early stage of reperfusion while necrosis at later stage during which both proapoptotic proteins, such as Bax, caspase-3 and antiapoptotic proteins, such as Bcl-2, play critical role in above-mentiond process. Hydrogen sulfide(H2S) was identified as the third gaseous mediator following the nitric oxide(NO) and carbon monoxide(CO), which is also synthesized in mammals including human and plays a variety of physiological activities. H2 S was especially discussed for its roles in cardiovascular system such as relaxing blood vessels, inhibiting proliferation of smooth muscle cells and protecting heart against ischemia-reperfusion injury.However, sodium hydrosulfide(Na HS), when dissolved in water, releases copious amounts of H2 S over a short time frame(seconds) and has cytoxic effect, thus may not effectively mimic the time course of H2 S releasing in vivo. GYY4137(morpholin-4-ium-methoxyphenyl-morpholino-phosphinodithioate) is a H2 S donor which releases H2 S slowly(in hours) in aqueous solution and may effectively mimic the time course of H2 S releasing in vivo. Recent years the effects of GYY4137 on antihypertension, protecting against endotoxic shock and inhibiting lipopolysaccharide-induced formation of inflammatorymediators in macrophages have been identified. In this study, we hypothesized that GYY4137 protected against MIRI in rats through downregulating MAPK signaling pathway, reducing oxidative stress and apoptosis.Male Sprague-Dawlay rats, 8-10 week old, were randomly grouped to be pretreated with pretreated with GYY4137(12.5mg/kg/day, 25mg/kg/day, 50mg/kg/day, ip.) for 9 days then subjected to myocardial ischemia induced by left anterior descending(LAD) coronary artery occlusion for 30 min followed by reperfusion for 24 hr. Myocardial function of rats in medium and high dose groups was significantly improved compared with vehicle treated group as well as reduced myocardial infarct size. Both plasma hydrogen sulfide concentration and myocardial CSE activity of GYY4137 treated groups were elevated significantly compared with vehicle treated group while serum malondialdehyde(MDA), myeloperoxidase(MPO) and cretine kinase(CK) levels were significantly reduced. Histopathological injury and superoxide anion level were attenuated in the myocardial sections of rats treated with medium and high dose GYY4137. We found that GYY4137 restrained the increase in levels of p-ERK, p-JNK and p-P38 in vehicle treated group after myocardial ischemia and reperfusion. We observed apoptosis by TUNEL stainning on paraffin embedded myocardium sections and found that extent of apoptosis was attenuated in medium and high dose GYY4137 treated groups compared with vehicle group, consistent with the result that GYY4137 upregulated protein level of Bcl-2 and downregulated Bax and also reduced caspase-3 activity in medium and high dose. This study proven that GYY4137 protected myocardial I/R injury through inhibiting MAPK signaling pathway, oxidative stress, apoptosis, and provides a new theoretical foundation for the protection of GYY4137 in MIRI. |
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