Role of STAT3 in ischemic preconditioning

We recently demostrated that ischemic preconditioning (IPC) induced by cycl ic episodes of short durations of ischemia and reperfusion potentiates a si gnal transduction cascade involving protein tyrosine kinases and MAP kinase s. A rapid activation of janus kinase (JAK) and several signal transducers and activators of the transcription (STATs) including STAT3, STAT5A and STA T6 has been shown to occur during myocardial ischemia and reperfusion. This study sought to examine if JAK/STAT signaling pathway play any role in cla ssical early phase of IPC. Isolated working rat hearts were perfused for 15 min with KHB buffer in the absence or presence of a JAK kinase inhibitor t yrphostin AG490 (5 muM) followed by IPC, 30 min global ischemia and 2 h of reperfusion. The results demonstrated extensive phosphorylation of JAK2 and STAT3 in the IPC hearts which was almost completely abolished by an inhibi tor of JAK2, AG490. IPC displayed cardioprotection as evidenced by improved post-ischemic contractile recovery, decreased myocardial infarct size and reduced number of apoptotic cardiomyocytes. AG490 blocked IPC-mediated card ioprotection by altering the IPC-mediated survival signal into death signal . Thus, IPC-induced upregulation of antiapoptotic gene bcl-2 and downregula tion of pro-apoptotic gene bax are decreased and increased, respectively, i n the AG490 treated hearts. The results suggest that early phase of IPC pot entiates JAK/STAT signaling by activating STAT3 which transmits a survival signal to the myocardium. (C) 2001 Academic Press.