Effect of HIF-1α/miR-10b-5p/PTEN on Hypoxia-Induced Cardiomyocyte Apoptosis

• Published in: Journal of the American Heart Association 2019-09, Vol.8 (18), p.e011948-e011948
• Main Authors: Wu, Liping, Chen, Yafen, Chen, Yuanyuan, Yang, Wenbo, Han, Yanxin, Lu, Lin, Yang, Ke, Cao, Jiumei
• Format: Article
• Language: English
• Subjects: acute myocardial infarction; Animals; apoptosis; Apoptosis - genetics; Hypoxia - genetics; Hypoxia - metabolism; Hypoxia-Inducible Factor 1, alpha Subunit - metabolism; hypoxia‐inducible factor 1α; Mice; Mice, Inbred C57BL; microRNA miR‐10b‐5p; MicroRNAs - metabolism; Myocardial Infarction - genetics; Myocardial Infarction - metabolism; Myocardial Reperfusion Injury - genetics; Myocardial Reperfusion Injury - metabolism; Myocytes, Cardiac - metabolism; Original Research; phosphatase and tensin homolog; PTEN Phosphohydrolase - metabolism
• ISSN: 2047-9980; 2047-9980
• DOI: 10.1161/JAHA.119.011948

Background Few reports have addressed the mechanism by which microRNA miR-10b-5p regulates post-myocardial infarction (post-MI) cardiomyocyte apoptosis under hypoxic conditions. Methods and Results C57BL/6 mice underwent surgical ligation of the left anterior descending artery to create an MI or ischemia/reperfusion animal model. The expression of miR-10b-5p, PTEN (phosphatase and tensin homolog), and HIF-1α (hypoxia-inducible factor 1α) was detected in infarct border zone tissues at various time points. After precordial injections of the negative control or miR-10b-5p, overexpression lentiviruses were made in the areas surrounding the MI sites at 1 week, and myocardial infarct size, cardiac function, and cardiomyocyte apoptosis were examined. A miR-10b-5p mimic was transfected into primary mouse cardiomyocytes to analyze its effects on cardiomyocyte apoptosis and PTEN expression. Meanwhile, PTEN as a target of miR-10b-5p was verified via luciferase reporter gene assays. Cotransfection of miR-10b-5 and PTEN verified the relationship between miR-10b-5 and PTEN. Under hypoxic stress, the expression of HIF-1α and miR-10b-5p was examined. The results showed that miR-10b-5p expression was markedly reduced in the infarct border zone. Overexpression of miR-10b-5p in the murine model of MI significantly reduced MI size, improved cardiac function, and inhibited apoptosis. Overexpression of miR-10b-5p in vitro antagonized hypoxia-induced cardiomyocyte apoptosis and specifically inhibited the expression of the apoptosis-related gene PTEN, but overexpression of PTEN weakened these effects. We also found that hypoxia-induced accumulation of HIF-1α resulted in decreased expression of miR-10b-5p. Interfering with the activation of the HIF-1α signaling pathway promoted Pri-miR-10b and miR-10b-5p expression and inhibited PTEN expression. Conclusions MicroRNA miR-10b-5p antagonizes hypoxia-induced cardiomyocyte apoptosis, indicating that miR-10b-5p may serve as a potential future clinical target for the treatment of MI.