Forkhead box O3 protects the heart against paraquat-induced aging-associated phenotypes by upregulating the expression of antioxidant enzymes
Forkhead box O3 protects the heart against paraquat-induced aging-associated phenotypes by upregulating the expression of antioxidant enzymes
复制标题
Forkhead box O3 通过上调抗氧化酶的表达来保护心脏免受百草枯诱导的衰老相关表型的影响
DOI：
10.1111/acel.12990
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发表时间：
2019-07-01
期刊：
影响因子：
7.8
通讯作者：
Qi, Xu-Feng
中科院分区：
文献类型：
--
作者：
Chang, Zao-Shang;Xia, Jing-Bo;Qi, Xu-Feng
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 beta-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. Overexpression of FoxO3 and CAT in hearts greatly suppressed the PQ-induced heart injury and phenotypes associated with aging. Collectively, these results suggest that FoxO3 protects the heart against an aging-associated decline in cardiac function in mice exposed to PQ, at least in part by upregulating the expression of antioxidant enzymes and suppressing oxidative stress.
