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.
Highlights
Acute myocardial infarction (AMI) is one of the main causes of morbidity and mortality in coronary heart disease
We previously showed that adiponectin (APN), a protein secreted from adipocytes and cardiomyocytes, is essential in ischemic postconditioning- (IPo-)mediated mitochondrial signal transducer and activator of transcription 3 (STAT3) activation and the subsequent protection against myocardial IR injury [3]
These protective effects of gAd were cancelled by either AMPactivated protein kinase (AMPK) inhibition with the specific inhibitor compound C (CC) or by STAT3 inhibition with the specific inhibitor stattic (Figures 1(a)–1(e))
Summary
Acute myocardial infarction (AMI) is one of the main causes of morbidity and mortality in coronary heart disease. STAT3 can be activated through phosphorylation at two residues: serine (Ser) 727 and tyrosine (Tyr) 705. When phosphorylated at Tyr705, STAT3 translocates into the nucleus where it promotes transcription of cardioprotective genes and improves cellular antioxidant property [6]. Cardiomyocyte-restricted STAT3 deletion rendered the hearts more sensitive to lipopolysaccharide-induced inflammatory damage [8]. All these indicate an important role of STAT3 activation in myocardial protection. Effective means that can activate STAT3 may attenuate myocardial IR injury through concomitantly reducing oxidative stress by improving mitochondrial biogenesis [9] and increasing antioxidant capacity by promoting the expression of nuclear antioxidant genes
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