Interleukin-6 induces upregulation of BNIP3 in cardiomyocytes to protect against myocardial ischemia/reperfusion injury.

Myocardial ischemia/reperfusion (I/R) injury primarily results from mitochondrial dysfunction and cardiomyocyte death. Mitophagy helps maintain mitochondrial function and offers protective effects to reperfused cardiac tissue. Interleukin-6 (IL-6), a cytokine released in response to acute injury, is expressed by multiple cell types, including cardiomyocytes. Recombinant IL-6 has been shown to limit myocardial infarctions in mice, suggesting its cardioprotective potential. This study aimed to explore the role of mitophagy in IL-6-induced cardioprotection and the underlying cellular mechanisms. Our findings revealed that silencing IL-6 with cardiotropic recombinant adeno-associated virus serotype 9 (rAAV9) in mouse hearts led to a significant increase in infarct sizes during myocardial I/R. We assessed mitophagy by analyzing mitophagy flux and related proteins. The results indicated that IL-6 knockdown notably reduced mitophagy induced by myocardial I/R both in vivo and in vitro. Additionally, myocardial I/R caused a significant rise in Bcl-2/adenovirus E1B 19-kDa interacting protein 3 (BNIP3), which was reversed by IL-6 silencing. Importantly, BNIP3 deficiency countered the mitophagy induced by recombinant IL-6 and nullified its cardioprotective effects. Mechanistically, IL-6 was shown to enhance the translocation of forkhead transcription factor Foxo3a to the nucleus, which increased the transcriptional activity of Foxo3a, leading to elevated BNIP3 levels in cardiomyocytes. BNIP3 was identified as a transcriptional target of Foxo3a, with Foxo3a binding to the BNIP3 promoter to activate its transcription. Notably, deletion of Foxo3a reduced the cardioprotective effects of recombinant IL-6. Based on these results, we propose that direct stimulation of mitophagy represents a novel mechanism through which IL-6 protects cardiomyocytes from myocardial I/R injury.