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 p16INK4a expression, were significantly enhanced by FoxO3 deficiency in cardiomyocytes. Notably, PQ‐induced cardiac remolding, apoptosis, oxidative damage, and p16INK4a 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.

Highlights

  • Oxidative stress is one of the most prominent hallmarks of aging and is characterized by the combination of higher reactive oxygen species (ROS) generation and impaired antioxidant defense (Kirkwood, 2005; Sohal & Weindruch, 1996)

  • We found that the expression of Cat and Sod2 was increased in shNC cells exposed to PQ compared with untreated cells; Forkhead box O3 (FoxO3) deficiency remarkably inhibited the PQ‐induced expression (Figure S2A–C), suggesting that FoxO3 may protect H9c2 cells from PQ‐mediated oxidative stress by regulating the expression of anti‐oxidases including CAT and superoxide dismutase 2 (SOD2)

  • We evaluated the effect of FoxO3 on PQ‐induced cardiac dysfunction and explored the potential mechanisms

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Summary

Introduction

Oxidative stress is one of the most prominent hallmarks of aging and is characterized by the combination of higher reactive oxygen species (ROS) generation and impaired antioxidant defense (Kirkwood, 2005; Sohal & Weindruch, 1996). We report that PQ exposure results in oxidative stress in cultured cardiomyocyte cell lines and hearts, and this is accompanied by phenotypes associated with senescence and aging, including proliferation arrest, apoptosis, cardiac remodeling, and dysfunction, as well as p16INK4a elevation.

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