Differential Regulation of Apoptosis by Ischemia‐Reperfusion and Ischemic Adaptation^a

Abstract

Ischemia and reperfusion injure the heart, as manifested by myocardial infarction, postischemic ventricular functional dysfunctions, arrhythmias, and cardiomyocyte apoptosis. Hearts can be adapted to ischemic-reperfusion injury by subjecting them to non-lethal cyclic episodes of short-term ischemia and reperfusion. The adapted myocardium becomes resistant to subsequent lethal ischemic injury. Reactive oxygen species and oxidative stress play crucial roles in the pathophysiology of ischemic-reperfusion injury. The adapted hearts, when subjected to subsequent ischemia and reperfusion, generate a reduced amount of oxygen free radicals compared to the nonadapted hearts. The number of cardiomyocytes undergoing apoptotic cell death is reduced in the adapted hearts subjected to ischemia and reperfusion. In concert, the adapted myocardium is associated with increased antioxidant gene Bcl-2, increased binding activity of the nuclear transcription factor NF kappa B, and reduced binding activity of AP-1 compared to nonadapted hearts. Yet when nonadapted hearts are subjected to ischemia and reperfusion, Bcl-2 is down-regulated while NF kappa B is moderately upregulated and AP-1 is significantly upregulated.