Adiponectin Facilitates Postconditioning Cardioprotection through Both AMPK-Dependent Nuclear and AMPK-Independent Mitochondrial STAT3 Activation

Abstract

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 involves adiponectin (APN). APN confers its biological effects through AMP-activated protein kinase- (AMPK-) dependent and AMPK-independent pathways. However, the role of AMPK in APN-mediated STAT3 activation in IPo cardioprotection is unknown. We hypothesized that APN-mediated STAT3 activation in IPo is AMPK-independent and that APN through AMPK-dependent STAT3 activation facilitates IPo cardioprotection. Here, Sprague-Dawley rats were subjected to myocardial IR without or with IPo and/or APN. APN or IPo significantly improved postischemic cardiac function and reduced myocardial injury and oxidative stress, and their combination further attenuated postischemic myocardial injuries. APN or its combination with IPo but not IPo alone significantly increased AMPK activation and both nuclear and mitochondrial STAT3 activation, while IPo significantly enhanced mitochondrial but not nuclear STAT3 activation. In primarily isolated cardiomyocytes, recombined globular APN (gAd), hypoxic postconditioning (HPo), or their combination significantly attenuated hypoxia/reoxygenation-induced cell injury and increased nuclear and/or mitochondrial STAT3 activation. STAT3 inhibition had no impact on gAd or gAd in combination with HPo-induced AMPK activation but abolished their cellular protective effects. AMPK inhibition did not affect HPo cardioprotection but abolished gAd cardioprotection and disabled gAd to facilitate/enhance HPo cardioprotection and STAT3 activation. These results suggest that APN confers cardioprotection through AMPK-dependent and AMPK-independent STAT3 activation, while IPo confers cardioprotection through AMPK-independent mitochondrial STAT3 activation. Joint use of APN and IPo synergistically attenuated myocardial IR injury by activating STAT3 via distinct signaling pathways.

Regulation of STAT3 and its role in cardioprotection by conditioning: focus on non-genomic roles targeting mitochondrial function

“…These authors were interested in the involvement of 5' Adenosine Monophosphate-activated protein kinase (AMPK) in IPostC and they found that STAT3 phosphorylation was not affected by the inhibition of AMPK, as well as the protective effects of IPostC were not abrogated, suggesting that IPostC in vitro relies on STAT3 and this is independent of AMPK signaling. In vivo model of MI achieved with LAD occlusion gave similar results with IPostC, increasing the level of S727 but not Y705 phosphorylation of STAT3 [ 250 ]. Moreover, they compared IPostC to pharmacological postconditioning with Adiponectin and they found that while IPostC induced STAT3 activation by S727 phosphorylation, the latter activated/phosphorylated STAT3 in Y705, supporting the difference between ischemic and pharmacological conditioning.…”

“…Zhu et al [ 250 ] found that IPostC, in primary rat ventricular cardiomyocytes exposed to H/R, is able to reduce H/R-induced cell damage, with concomitant enhancement of STAT3 phosphorylation S727 but not at Y705. These authors were interested in the involvement of 5' Adenosine Monophosphate-activated protein kinase (AMPK) in IPostC and they found that STAT3 phosphorylation was not affected by the inhibition of AMPK, as well as the protective effects of IPostC were not abrogated, suggesting that IPostC in vitro relies on STAT3 and this is independent of AMPK signaling.…”

“…Moreover, they compared IPostC to pharmacological postconditioning with Adiponectin and they found that while IPostC induced STAT3 activation by S727 phosphorylation, the latter activated/phosphorylated STAT3 in Y705, supporting the difference between ischemic and pharmacological conditioning. Interestingly, the combination of IPostC and Adiponectin conditioning provided additional protection in comparison with the conditioning alone, and promoted the phosphorylation of both sites of STAT3 [ 250 ]. This suggests that the integration of canonical pathway of STAT3 (transcription of antioxidant and anti-apoptotic genes) with the mitochondrial pathway (reduction of ROS production, mPTPs opening prevention, optimization of complex I activity) is able to provide maximal cardioprotection in vivo.…”

Ischemic Postconditioning-Mediated DJ-1 Activation Mitigate Intestinal Mucosa Injury Induced by Myocardial Ischemia Reperfusion in Rats Through Keap1/Nrf2 Pathway

“…IPo was established by the group of Vinten-Johansen (Zhao et al, 2003) who first reported 3 cycles of 30 s reperfusion/30 s reocclusion immediately at the onset of reperfusion after 60 min of LAD occlusion. A recent study showed that 3 cycles of 10 s of reocclusion and 10 s of reperfusion at the onset of reperfusion conferred cardioprotection by reducing ROS production through AMPKindependent activation of STAT3 at Ser727 (Zhu et al, 2020). The myocardial protective effect of IPo also relies on regulating energy homeostasis and the expression of myocardial mitochondrial proteins (Cao et al, 2016).…”

Tissue-specific role and associated downstream signaling pathways of adiponectin

“…Adiponectin treatment is shown to induce the activation of ceramidase (CDase) and subsequently prevents apoptosis of isolated ventricular cardiomyocytes from obese mice through the degradation of ceramides [ 60 ]. Adiponectin has been shown to involve myocardial ischemic postconditioning (IPo)-mediated cardioprotection against myocardial ischemia–reperfusion (IR) injury in rodents via both AMPK-dependent nuclear and AMPK-independent mitochondrial signal transducer and activator of transcription (STAT)3 activation [ 61 ]. Adipo KO mice exhibited enhanced myocardial apoptosis, infract size, levels of nitric oxide (NO), inducible nitric oxide synthase (iNOS), superoxide, and their cytotoxic reaction products, peroxynitrite, in cardiac tissues [ 62 ].…”