Abstract 17237: Synergistic Reduction of Myocardial Ischemia Reperfusion Injury by Ischemic Preconditioning and Myocardial SOCS3 Deficiency in Mice

Introduction: Ischemic preconditioning (IPC) has cardiac protective effects. However, the effect is not certain in clinical trials and the inhibitory mechanism underlying the cardioprotection by IPC remains unknown. Suppressor of cytokine signaling-3 (SOCS3) is a cytokine-inducible negative regulator of JAK-STAT signaling pathway. In this study, we investigated the role of myocardial SOCS3 against the ischemia reperfusion injury (IRI) during IPC. Hypothesis: We hypothesized that IPC combination with myocardial SOCS3 deficiency would have synergistic effects in the reduction of myocardial injury after IRI. Methods: Myocardial IPC was elicited by three cycles of 5 min left ascending coronary artery occlusion and 5 min reperfusion, and after the IPC, the coronary artery was reoccluded to induce ischemia reperfusion injury. The infarct size was estimated by evans blue dye and triphenyltetrazolium chloride staining. We precisely evaluated the phosphorylation of STAT3 and the expression of SOCS3 after IPC in wild-type (WT) and cardiac-specific SOCS3 knockout mice (SOCS3-CKO). Results: STAT3 phosphorylation was faint immediately after IPC, marked at 1 h after IPC, and suppressed at 3 h after IPC; this transient activation of STAT3 was closely correlated with the induction of SOCS3 expression in WT. In contrast, STAT3 phosphorylation after IPC was significantly greater and sustained in SOCS3-CKO than in WT ( p Western blot analysis revealed that anti-apoptotic Bcl-xL and myeloid cell leukemia-1 (Mcl-1) expression after myocardial ischemia reperfusion injury were significantly increased in SOCS3-CKO/IPC (+) compared with WT/IPC(+) ( p Conclusions: Thus, myocardial SOCS3 deficiency and IPC have synergistic effects in the reduction of myocardial injury after IRI. Our results suggest that IPC combination with myocardial SOCS3 inhibition may be a novel strategy for the reduction of myocardial injury after IRI.