Forkhead box O3 protects the heart against paraquat‐induced aging‐associated phenotypes by upregulating the expression of antioxidant enzymes

作者：Zao‐Shang Chang, Jingbo Xia, Haiyan Wu, Wentao Peng, Fu‐Qing Jiang, Jing Li, Chi‐Qian Liang, Hui Zhao, Kyu‐Sang Park, Guohua Song, Soo‐Ki Kim, Ruijin Huang, Li Zheng, Dongqing Cai, Xufeng Qi · 发表于：Aging Cell · 年份：2019 · DOI：10.1111/acel.12990 · 被引用次数：82 · 研究领域：FOXO transcription factor regulation、Plant Stress Responses and Tolerance、PARP inhibition in cancer therapy

Abstract Paraquat (PQ) promotes cell senescence in brain tissue, which contributes to Parkinson's disease. Furthermore, PQ induces heart failure and oxidative damage, but it remains unknown whether and how PQ induces cardiac aging. Here, we demonstrate that PQ induces phenotypes associated with senescence of cardiomyocyte cell lines and results in cardiac aging‐associated phenotypes including cardiac remodeling and dysfunction in vivo. Moreover, PQ inhibits the activation of Forkhead box O3 (FoxO3), an important longevity factor, both in vitro and in vivo. We found that PQ‐induced senescence phenotypes, including proliferation inhibition, apoptosis, senescence‐associated β‐galactosidase activity, and p16 INK4a expression, were significantly enhanced by FoxO3 deficiency in cardiomyocytes. Notably, PQ‐induced cardiac remolding, apoptosis, oxidative damage, and p16 INK4a expression in hearts were exacerbated by FoxO3 deficiency. In addition, both in vitro deficiency and in vivo deficiency of FoxO3 greatly suppressed the activation of antioxidant enzymes including catalase (CAT) and superoxide dismutase 2 (SOD2) in the presence of PQ, which was accompanied by attenuation in cardiac function. The direct in vivo binding of FoxO3 to the promoters of the Cat and Sod2 genes in the heart was verified by chromatin immunoprecipitation (ChIP). Functionally, overexpression of Cat or Sod2 alleviated the PQ‐induced senescence phenotypes in FoxO3‐deficient cardiomyocyte cell lines. Overexpres...