Studies On Cardiomyocyte Apoptosis In Myocardial Injury

1. The Role of Nitric Oxide at Different Time Point in Myocardial Ischemia and Reperfusion InjuryBackground and objectivesPersistent myocardial ischemia without reperfusion inevitably results in myocyte cell death. Although the beneficial effects of early restoration of blood flow to ischemic myocardium are now well established, results of an increasing number of studies indicate that reperfusion has deleterious effects on the ischemic myocardium such as regional inflammatory reaction, necrosis and apoptosis that can accelerate and extend post-ischemic injury. Herein lies the concept of reperfusion injury. Nitric oxide (NO), an endogenous free radical that can be produced in all cell types, is synthesized from L-arginine by NO synthase (NOS). A great number of researches indicate that NO plays an important role in myocardial ischemia and reperfusion (MI/R).However, both protective and deleterious effects of NO on ischemia/reperfusion injury have been published and the mechanisms responsible for this diversity remain largely unknown. Our previous studies have demonstrated that supplementation of L-arginine during different stages of reperfusion has opposing effects on myocardial apoptosis after MI/R. Early supplementation of L-arginine can inhibit cardiomyocyte apoptosis, whereas L-arginine promotes apoptosis if administered during the late phase of reperfusion when inducible NOS (iNOS) is expressed. However, whether the opposing effects of L-arginine administration at different time point on post-ischemic apoptosis may translate into a clinically meaningful protection/damage on cardiac contractile function remains unknown. In addition, the cellular origin (i.e., infiltrated inflammatory cells vs. cardiomyocytes) of iNOS and toxic RNS has not been identified. Polymorphonuclear leukocyte (PMN) accumulation/activation has been implicated as a primary mechanism underlying MI/R injury. Recent studies have demonstrated that PMNs express inducible nitric oxide synthase (iNOS) and produce toxic reactive nitrogen species (RNS). However, the role of iNOS-derived reactive nitrogen species and resultant nitrative stress in PMN-induced cardiomyocyte apoptosis after myocardial ischemia/reperfusion remains unclear.Therefore, the objectives of the present study were (1) to determine whether early supplementation of L-arginine may ameliorates post-ischemic cardiac function, and if so, to clarify the relationship between NO production and L-arginine's protective effect; (2) to elucidate whether the supplementation of L-arginine during a late phase of reperfusion may aggravate post-ischemic cardiac function, and if so, to identify the mechanisms involved; and (3) to investigate whether PMN-originated iNOS and RNS may contribute to post-ischemic nitrative...