Research Paper Volume 13, Issue 3 pp 3443—3458
Hypoxia-inducible factor 2-alpha-dependent induction of IL-6 protects the heart from ischemia/reperfusion injury
- 1 Department of Cardiology, The First Affiliated Hospital of USTC, Division of Life Science and Medicine, University of Science and Technology of China, Hefei 230001, China
Received: April 28, 2020 Accepted: September 5, 2020 Published: January 10, 2021https://doi.org/10.18632/aging.202276
How to Cite
Copyright: © 2021 Wu et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Myocardial ischemia-reperfusion injury (MIRI) results in increased myocardial infarct size and leads to poor clinical outcomes. Hypoxia-inducible factor 2-alpha (HIF2α) exerts myocardial protective effects during MIRI through as yet unclear mechanisms. Here, we show that knockdown of HIF2α with cardiotropic recombinant adeno-associated virus serotype 9 (rAAV9) in mouse hearts significantly increased the infarct sizes during myocardial ischemia/reperfusion (MI/R). In addition, HIF2α transcriptionally regulated the expression of interleukin 6 (IL-6) in cardiomyocytes to elicit cardioprotection. Likewise, IL-6 deficiency aggravated MIRI, while treatment with recombinant IL-6 had cardioprotective effects and rescued the mice with HIF2α knockdown. Furthermore, IL-6 treatment significantly activated the PI3K/Akt and STAT3 signaling pathways in the myocardium during MI/R, and the specific inhibitors wortmannin (specific phosphoinositide 3-kinase inhibitor) and Stattic (specific STAT3 inhibitor) substantially abolished HIF2α/IL-6-induced cardioprotection. These studies suggest that HIF2α transcription regulates the expression of IL-6 in cardiomyocytes and plays a protective role during MI/R.