FOSTRIECIN, AN INHIBITOR OF PROTEIN PHOSPHATASE 2A, LIMITS MYOCARDIALINFARCT SIZE EVEN WHEN ADMINISTERED AFTER ONSET OF ISCHEMIA

Background-The role of protein phosphatases (PPs) during ischemic prec onditioning in the rabbit heart was examined. Methods and Results-Fost riecin, a potent inhibitor of PP2A, was administered to isolated rabbi t hearts starting either 15 minutes before or 10 minutes after the ons et of a 30-minute period of regional ischemia and continuing until the onset of reperfusion. After 2 hours of reperfusion, infarct size was measured with triphenyltetrazolium chloride. In a second study with is olated rabbit cardiomyocytes, the effect of fostriecin pretreatment wa s assessed by measuring changes in cell osmotic fragility during simul ated ischemia. PP1 and PP2A activities of isolated control and ischemi cally preconditioned cells were also measured. In a third series of ex periments, left ventricular biopsies of isolated rabbit hearts were ob tained before and at selected times during 60 minutes of global ischem ia, and the tissue was assayed for PP1 and PP2A activities, In isolate d hearts pretreated with fostriecin, only 8% of the ischemic zone infa rcted, significantly less than that in untreated control hearts (33%; P<0.001) but comparable to that in ischemically preconditioned hearts (9%; P<0.001 versus control). Significant protection was also observed in the hearts treated only after the onset of ischemia (18% infarctio n; P<0.05 versus control), In isolated myocytes, fostriecin also provi ded protection comparable to that produced by metabolic preconditionin g. Preconditioning had no apparent effect on the activity of either PP 1 or PP2A in isolated ventricular myocytes or ventricular tissue obtai ned from heart biopsies. Conclusions-Fostriecin, a potent inhibitor of PP2A, can protect the rabbit heart from infarction even when administ ered after the onset of ischemia. But inhibition of either PP1 or PP2A does not appear to be the mechanism of protection from ischemic preco nditioning.