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.
Aging (Albany NY). 2021 Jan 10;13(3):3443-3458. doi: 10.18632/aging.202276.
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.
心肌缺血再灌注损伤（MIRI）导致心肌梗死面积增加，并导致临床预后不良。缺氧诱导因子 2-α（HIF2α）通过尚不清楚的机制在 MIRI 期间发挥心肌保护作用。在这里，我们表明，在小鼠心脏中用心脏靶向重组腺相关病毒血清型 9（rAAV9）敲低 HIF2α会显著增加心肌缺血/再灌注（MI/R）期间的梗死面积。此外，HIF2α转录调控心肌细胞中白细胞介素 6（IL-6）的表达以产生心脏保护作用。同样，IL-6 缺乏加重了 MIRI，而重组 IL-6 的治疗具有心脏保护作用，并挽救了 HIF2α 敲低的小鼠。此外，IL-6 治疗在 MI/R 期间显著激活了心肌中的 PI3K/Akt 和 STAT3 信号通路，特异性抑制剂wortmannin（特异性磷脂酰肌醇 3-激酶抑制剂）和 Stattic（特异性 STAT3 抑制剂）实质上消除了 HIF2α/IL-6 诱导的心脏保护作用。这些研究表明，HIF2α 转录调节心肌细胞中 IL-6 的表达，并在 MI/R 期间发挥保护作用。
