ocardial stunning, acute diastolic dysfunction, cellular calcium overload, re energization induced myocyte hypercontracture, arrhythmia, and cell death. There is marked overactivation of PARP in the reperfused myocardium, which parallels with the decline FGFR 1 of the contractile function and myocardial NAD and ATP contents in preclinical models of myocardial infarction and cardiopulmonary bypass. Consequently, the pharmacological inhibition of PARP with various inhibitors or genetic deletion of PARP 1 in mice, rats, rabbits, dogs, and pigs markedly improves the outcome of myocardial ischemia reperfusion damage associated with hypoxia/reoxygenation, coronary artery occlusion/reocclusion, cardiopulmonary bypass, and cardiac transplantation, which is also a subject of numerous recent overviews.
The favorable effects of PARP inhibitors in these preclinical models involve improvement in myocardial Receptor Tyrosine Kinase intracellular energy status and myocardial contractility, attenuation of the proinflammatory gene/mediator expression and neutrophil infiltration into the reperfused myocardium, and decrease of cardiomyocyte and endothelial cell necrosis. Several recent human studies have investigated the role of peroxynitrite also known to be an obligatory trigger of oxidative DNA damage and consequent PARP activation, in myocardial ischemia/reperfusion in patients undergoing open heart surgery. These studies analyzed myocardial nitrotyrosine immunoreactivity from left ventricular biopsy specimen or plasma nitrotyrosine levels from coronary sinus effluent and/or arterial blood before and at the end of cardiopulmonary bypass.
They found that the difference between plasma nitrotyrosine level from coronary sinus effluent and arterial blood peaked at 5 minutes following reperfusion, and was significantly correlated with the peak coronary sinus effluent and arterial blood difference in plasma malondialdehyde concentrations, and with postoperative maximum creatinine kinase level. The cardioplegia induced myocardial I/R was also accompanied by increased iNOS expression, nitrotyrosine and 9 isoprostane formation, further supporting the role of both peroxynitrite and reactive oxygen species in mediating the myocardial injury.
Increased immunostaining for nitrotyrosine and iNOS were also demonstrated from the left ventricular biopsy specimens of patients with hibernating myocardium, a state of chronic contractile dysfunction present at rest in a territory subtended by a stenosed coronary artery that recovers following revascularization, most likely originated from repetitive episodes of transient ischemia, and in human coronaryarteries of patients with human transplant coronary artery disease, a major cause of late mortality after cardiac transplantation, and during cardiac allograft rejection. At present, human studies have not yet been conducted to investigate if PARP is activated in human cardiomyocytes and endothelial cells during the myocardial reperfusion injury. Nevertheless, a recent study investigated multiple aspects of human myocardial ischemia/reperfusion related pathology by analyzing serum, plasma, and isolated peripheral leukocyte samples from cardiovascular patients with acute ST segment elevation myocardial infarction and successful primary angioplastic intervention