Adiponectin Through AMPK‐dependent Nuclear STAT3 Activation Facilitates Ischemic Postconditioning Cardioprotection
Authors: Zhu Qiqi , Li Haobo , Xie Xiang , Lian Qingquan , Ge Ren‐shan , Xia Zhengyuan 
Published: November 2023

Myocardial ischemic postconditioning (IPo) mediated cardioprotection against myocardial ischemia reperfusion (IR) injury needs the activation of signal transducer and activator of transcription 3 (STAT3), which can be achieved independent of AMP‐activated protein kinase (AMPK), a critical mediator in adiponectin (APN) cardioprotection. APN can activate STAT3 to confer cardioprotection. However, how the role of AMPK in APN mediated STAT3 activation is unknown. We hypothesized that APN activates STAT3 via AMPK and that APN through AMPK‐dependent STAT3 activation facilitates IPo cardioprotection.

Sprague Dawley rats were either sham‐operated or subjected to myocardial IR (30 min coronary occlusion followed by 120 min reperfusion) without or with IPo (3 cycles of 10s of ischemia and 10s of reperfusion, applied immediately at the onset of reperfusion) or APN (1×109 pfu, injected 7 days before inducing IR via tail vein) or their combination. At the end of reperfusion, APN, or IPo significantly improved post‐ischemic cardiac functional recovery evidenced by increased dP/dtmax that was associated with reduced myocardial injury manifested as reduced myocardial infarct size and plasma creatine kinase‐MB release (P<0.05 vs. IR), while APN in combination with IPo further attenuated post‐ischemic myocardial injury compared to their individual effects. APN or its combination with IPo but not IPo alone significantly increased AMPK activation and nuclear STAT3 activation at site Tyr705, while IPo or its combination with APN but not APN alone significantly enhanced mitochondrial STAT3 activation at site Ser727.

In primary isolated cardiomyocytes, application of APN (2 μmol/L, 24 hours before HR), hypoxic postconditioning (HPo, 3 cycles of 5 min hypoxia and 5 min reoxygenation), or their combination significantly attenuated hypoxia/reoxygenation (HR, 45 min hypoxia and 2 hours reoxygenation) induced cell injury evidenced by decreased lactate dehydrogenase release and reduced apoptotic cell death with concomitant reduced mitochondrial transmembrane potential (P<0.05 vs. HR). APN, HPo, or their combination significantly increased STAT3 activation. All these beneficial effects of APN, HPo, or their combination were abolished by specific STAT3 inhibition (stattic, 100 μmol/L, 10 min before HR). APN or its combination with HPo but not HPo alone significantly increased APMK activation. STAT3 inhibition has no impact on APN or its combination with HPo‐induced AMPK activation. Specific inhibition of AMPK (compound C, 5 μmol/L, 1 hour before HR) had no significant impact on cardioprotection conferred by HPo alone, but abolished APN cardioprotection and disabled APN to facilitate/enhance HPo cardioprotection, that was associated with attenuated STAT3 activation.

It is concluded that APN confers cardioprotection mainly through AMPK‐dependent nuclear STAT3 activation, while IPo confers cardioprotection mainly through mitochondrial STAT3 activation which is AMPK‐independent. Joint use of APN and IPo synergistically attenuated myocardial IR by activating STAT3 via distinct signaling pathways.

Support or Funding Information

This study was supported in part by the Hong Kong RGC/GRF grants (17124614M, 17123915M) and in part by the Zhejiang Provincial Top priority first level discipline grant, China.