Caveolin-3/AdipoR1 dependent mitochondrial STAT3 activation in ischemic postconditioning cardioprotection

Abstract

Ischemic postconditioning (IPo) protects against myocardial ischemic reperfusion (IR) injury by activating signal transducer and activator of transcription 3 (STAT3) which requires adiponectin (APN) (FASEB, 2014, 28: 663.7), but how APN activates STAT3 during IPo is unclear. Caveolin-3 (Cav3), a protein of the lipid rafts/caveolae, is essential in APN receptor 1 (AdipoR1) transmembrane signaling. We postulated that IPo activates mitochondrial STAT3 (mitoSTAT3) via Cav3 AdipoR1 signaling. Wild type (WT) and APN knockout (KO) mice were subjected to sham operation or IR (30min of coronary artery occlusion and 2 hours of reperfusion) with or without IPo (3 cycles of 10s of reperfusion and 10s of reocclusion). KO mice exhibited more severe myocardial injury (increased post-ischemic infarction and poorer functional recovery; P<0.05 vs. WT), impaired mitochondrial function and reduced mitoSTAT3 phosphorylation (p-mitoSTAT3). IPo attenuated post-ischemic cardiac injury and mitochondrial dysfunction and increased p-mitoSTAT3 in WT but not in KO mice. IPo increased Cav3 in buoyant membrane fraction and increased colocolazation of Cav3 with AdipoR1 but not AdipoR2 in both WT and KO mice (P<0.05 vs. IR). In cultured cardiac H9C2 cell, hypoxic postconditioning (HPo) attenuated hypoxia/reoxygenation (HR) induced cell injury and restored mitochondrial transmembrane potential, concomitant with increased p-mitoSTAT3 and Cav3 (P<0.05, vs. HR). Cav3 or AdipoR1 but not AdipoR2 gene knockdown abolished the above HPo beneficial effects. APN supplementation restored HPo protection in cells with APN gene knockdown but not in cells with Cav3 or AdipoR1 gene knockdown. It is concluded that IPo conferred cardioprotection through Cav3/AdipoR1 dependent mitoSTAT3 activation.