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

Zao Shang Chang, Jing Bo Xia, Hai Yan Wu, Wen Tao Peng, Fu Qing Jiang, Jing Li, Chi Qian Liang, Hui Zhao, Kyusang Park, Guo Hua Song, Soo-Ki Kim, Ruijin Huang, Li Zheng, Dong Qing Cai, Xu Feng Qi

Research output: Contribution to journalArticle

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.

Original languageEnglish
Article numbere12990
JournalAging Cell
Volume18
Issue number5
DOIs
Publication statusPublished - 2019 Oct 1

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Paraquat
Antioxidants
Phenotype
Enzymes
Cardiac Myocytes
Catalase
Cats
Galactosidases
Heart Injuries
Apoptosis
Cell Line
Enzyme Activation
Chromatin Immunoprecipitation
Cell Aging
Parkinson Disease
Oxidative Stress
Heart Failure

All Science Journal Classification (ASJC) codes

  • Ageing
  • Cell Biology

Cite this

Chang, Zao Shang ; Xia, Jing Bo ; Wu, Hai Yan ; Peng, Wen Tao ; Jiang, Fu Qing ; Li, Jing ; Liang, Chi Qian ; Zhao, Hui ; Park, Kyusang ; Song, Guo Hua ; Kim, Soo-Ki ; Huang, Ruijin ; Zheng, Li ; Cai, Dong Qing ; Qi, Xu Feng. / Forkhead box O3 protects the heart against paraquat-induced aging-associated phenotypes by upregulating the expression of antioxidant enzymes. In: Aging Cell. 2019 ; Vol. 18, No. 5.
@article{e822dfbef9734b769830cfddaae77c67,
title = "Forkhead box O3 protects the heart against paraquat-induced aging-associated phenotypes by upregulating the expression of antioxidant enzymes",
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.",
author = "Chang, {Zao Shang} and Xia, {Jing Bo} and Wu, {Hai Yan} and Peng, {Wen Tao} and Jiang, {Fu Qing} and Jing Li and Liang, {Chi Qian} and Hui Zhao and Kyusang Park and Song, {Guo Hua} and Soo-Ki Kim and Ruijin Huang and Li Zheng and Cai, {Dong Qing} and Qi, {Xu Feng}",
year = "2019",
month = "10",
day = "1",
doi = "10.1111/acel.12990",
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Chang, ZS, Xia, JB, Wu, HY, Peng, WT, Jiang, FQ, Li, J, Liang, CQ, Zhao, H, Park, K, Song, GH, Kim, S-K, Huang, R, Zheng, L, Cai, DQ & Qi, XF 2019, 'Forkhead box O3 protects the heart against paraquat-induced aging-associated phenotypes by upregulating the expression of antioxidant enzymes', Aging Cell, vol. 18, no. 5, e12990. https://doi.org/10.1111/acel.12990

Forkhead box O3 protects the heart against paraquat-induced aging-associated phenotypes by upregulating the expression of antioxidant enzymes. / Chang, Zao Shang; Xia, Jing Bo; Wu, Hai Yan; Peng, Wen Tao; Jiang, Fu Qing; Li, Jing; Liang, Chi Qian; Zhao, Hui; Park, Kyusang; Song, Guo Hua; Kim, Soo-Ki; Huang, Ruijin; Zheng, Li; Cai, Dong Qing; Qi, Xu Feng.

In: Aging Cell, Vol. 18, No. 5, e12990, 01.10.2019.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Forkhead box O3 protects the heart against paraquat-induced aging-associated phenotypes by upregulating the expression of antioxidant enzymes

AU - Chang, Zao Shang

AU - Xia, Jing Bo

AU - Wu, Hai Yan

AU - Peng, Wen Tao

AU - Jiang, Fu Qing

AU - Li, Jing

AU - Liang, Chi Qian

AU - Zhao, Hui

AU - Park, Kyusang

AU - Song, Guo Hua

AU - Kim, Soo-Ki

AU - Huang, Ruijin

AU - Zheng, Li

AU - Cai, Dong Qing

AU - Qi, Xu Feng

PY - 2019/10/1

Y1 - 2019/10/1

N2 - 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.

AB - 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.

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