Key Laboratory of Regenerative Medicine of Ministry of Education, Department of Developmental & Regenerative Biology, Jinan University, Guangzhou, China.
Department of Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
Aging Cell. 2019 Oct;18(5):e12990. doi: 10.1111/acel.12990. Epub 2019 Jul 1.
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 expression, were significantly enhanced by FoxO3 deficiency in cardiomyocytes. Notably, PQ-induced cardiac remolding, apoptosis, oxidative damage, and p16 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.
百草枯（PQ）促进脑组织中的细胞衰老，从而导致帕金森病。此外，PQ 会引起心力衰竭和氧化损伤，但尚不清楚 PQ 是否以及如何引起心脏衰老。在这里，我们证明 PQ 诱导与心肌细胞系衰老相关的表型，并导致体内与心脏衰老相关的表型，包括心脏重构和功能障碍。此外，PQ 抑制叉头框 O3（FoxO3）的激活，FoxO3 是一种重要的长寿因子，在体外和体内都是如此。我们发现，PQ 诱导的衰老表型，包括增殖抑制、凋亡、衰老相关的β-半乳糖苷酶活性和 p16 表达，在心肌细胞中 FoxO3 缺失时显著增强。值得注意的是，PQ 诱导的心脏重塑、凋亡、氧化损伤和 p16 表达在心脏中的表达在 FoxO3 缺失时加剧。此外，在存在 PQ 的情况下，体外和体内 FoxO3 的缺乏都极大地抑制了包括过氧化氢酶 (CAT) 和超氧化物歧化酶 2 (SOD2) 在内的抗氧化酶的激活，从而导致心脏功能减弱。FoxO3 在心脏中直接与 Cat 和 Sod2 基因的启动子结合，通过染色质免疫沉淀（ChIP）得到验证。功能上，Cat 或 Sod2 的过表达缓解了 FoxO3 缺陷型心肌细胞系中 PQ 诱导的衰老表型。FoxO3 和 CAT 在心脏中的过表达极大地抑制了 PQ 诱导的心脏损伤和与衰老相关的表型。总的来说，这些结果表明，FoxO3 通过上调抗氧化酶的表达和抑制氧化应激，保护心脏免受 PQ 暴露引起的与衰老相关的心脏功能下降，至少部分是这样。
