Anti-ischemic effect of a novel cardioprotective agent, JTV519, is mediated through specific activation of delta-isoform of protein kinase C in rat ventricular myocardium

Background-A new 1,4-benzothiazepine derivative, JTV519, has a strong prote ctive effect against Ca2+ overload-induced myocardial injury. We investigat ed the effect of JTV519 on ischemia/reperfusion injury in isolated rat hear ts. Methods and Results-At 30 minutes of reperfusion after 30-minute global isc hemia, the percent recovery of left ventricular developed pressure was impr oved, and the creatine phosphokinase and lactate dehydrogenase leakage was reduced in a concentration-dependent manner when JTV519 was administered in the coronary perfusate both at 5 minutes before the induction of ischemia and at the time of reperfusion, The myocardial protective effect of JTV519 was completely blocked by pretreatment of the heart with GF109203X, a speci fic protein kinase C (PKC) inhibitor. In contrast, the effect of JTV519 was not affected by alpha(1)-, A(1)-, and B-2-receptor blockers that couple wi th PKC in the cardiomyocyte. Both immunofluorescence images and immunoblots of JTV519-treated left ventricular myocardium and isolated ventricular myo cytes demonstrated that this agent induced concentration-dependent transloc ation of the delta-isoform but not the other isoforms of PKC to the plasma membrane, Conclusions-The mechanism of cardioprotection by JTV519 against ischemia/re perfusion injury involves isozyme-specific PKC activation through a recepto r-independent mechanism. This agent may provide a novel pharmacological app roach for the treatment of patients with acute coronary diseases via a subc ellular mechanism mimicking ischemic preconditioning.