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Cancer Innovation 2023, 2(4): 253-264 https://doi.org/10.1002/cai2.64
Original Article | Open Access | Issue | Published: 30 March 2023

Resveratrol activation of SIRT1/MFN2 can improve mitochondria function, alleviating doxorubicin‐induced myocardial injury

Show Author's Information Qingling Zhang1,,  Yunpeng Zhang1,,  Bingxin Xie1,  Daiqi Liu1,  Yueying Wang1,  Zandong Zhou1,  Yue Zhang1,  Emma King2,  Gary Tse1,2,3,  Tong Liu1 ( )
Department of Cardiology, Tianjin Key Laboratory of Ionic‐Molecular Function of Cardiovascular Disease, Tianjin Institute of Cardiology, The Second Hospital of Tianjin Medical University, Tianjin, China
Epidemiology Research Unit, Cardiovascular Analytics Group, China‐ UK Collaboration, Hong Kong, China
Kent and Medway Medical School, Canterbury, Kent, UK Correspondence

Qingling Zhang and Yunpeng Zhang contributed equally to this study and shared the first authorship.

Keywords:
resveratrol, cardio‐oncology, doxorubicin‐induced cardiomyopathy, mitochondria function, SIRT1 agonists
Cite this article:
Zhang Q, Zhang Y, Xie B, et al. Resveratrol activation of SIRT1/MFN2 can improve mitochondria function, alleviating doxorubicin‐induced myocardial injury. Cancer Innovation, 2023, 2(4): 253-264. https://doi.org/10.1002/cai2.64
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Abstract Full text Electronic supplementary material About this article
Background

Doxorubicin is a widely used cytotoxic chemotherapy agent for treating different malignancies. However, its use is associated with dose‐dependent cardiotoxicity, causing irreversible myocardial damage and significantly reducing the patient's quality of life and survival. In this study, an animal model of doxorubicin‐induced cardiomyopathy was used to investigate the pathogenesis of doxorubicin‐induced myocardial injury. This study also investigated a possible treatment strategy for alleviating myocardial injury through resveratrol therapy in vitro.

Methods

Adult male C57BL/6J mice were randomly divided into a control group and a doxorubicin group. Body weight, echocardiography, surface electrocardiogram, and myocardial histomorphology were measured. The mechanisms of doxorubicin cardiotoxicity in H9c2 cell lines were explored by comparing three groups (phosphate‐buffered saline, doxorubicin, and doxorubicin with resveratrol).

Results

Compared to the control group, the doxorubicin group showed a lower body weight and higher systolic arterial pressure, associated with reduced left ventricular ejection fraction and left ventricular fractional shortening, prolonged PR interval, and QT interval. These abnormalities were associated with vacuolation and increased disorder in the mitochondria of cardiomyocytes, increased protein expression levels of α‐smooth muscle actin and caspase 3, and reduced protein expression levels of Mitofusin2 (MFN2) and Sirtuin1 (SIRT1). Compared to the doxorubicin group, doxorubicin + resveratrol treatment reduced caspase 3 and manganese superoxide dismutase, and increased MFN2 and SIRT1 expression levels.

Conclusion

Doxorubicin toxicity leads to abnormal mitochondrial morphology and dysfunction in cardiomyocytes and induces apoptosis by interfering with mitochondrial fusion. Resveratrol ameliorates doxorubicin‐induced cardiotoxicity by activating SIRT1/MFN2 to improve mitochondria function.


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Abstract
Full text
Outline
Electronic supplementary material
About this article

Resveratrol activation of SIRT1/MFN2 can improve mitochondria function, alleviating doxorubicin‐induced myocardial injury

Show Author's information Qingling Zhang1,, Yunpeng Zhang1,, Bingxin Xie1, Daiqi Liu1, Yueying Wang1, Zandong Zhou1, Yue Zhang1, Emma King2, Gary Tse1,2,3, Tong Liu1 ( )
Department of Cardiology, Tianjin Key Laboratory of Ionic‐Molecular Function of Cardiovascular Disease, Tianjin Institute of Cardiology, The Second Hospital of Tianjin Medical University, Tianjin, China
Epidemiology Research Unit, Cardiovascular Analytics Group, China‐ UK Collaboration, Hong Kong, China
Kent and Medway Medical School, Canterbury, Kent, UK Correspondence

Qingling Zhang and Yunpeng Zhang contributed equally to this study and shared the first authorship.

Abstract

Background

Doxorubicin is a widely used cytotoxic chemotherapy agent for treating different malignancies. However, its use is associated with dose‐dependent cardiotoxicity, causing irreversible myocardial damage and significantly reducing the patient's quality of life and survival. In this study, an animal model of doxorubicin‐induced cardiomyopathy was used to investigate the pathogenesis of doxorubicin‐induced myocardial injury. This study also investigated a possible treatment strategy for alleviating myocardial injury through resveratrol therapy in vitro.

Methods

Adult male C57BL/6J mice were randomly divided into a control group and a doxorubicin group. Body weight, echocardiography, surface electrocardiogram, and myocardial histomorphology were measured. The mechanisms of doxorubicin cardiotoxicity in H9c2 cell lines were explored by comparing three groups (phosphate‐buffered saline, doxorubicin, and doxorubicin with resveratrol).

Results

Compared to the control group, the doxorubicin group showed a lower body weight and higher systolic arterial pressure, associated with reduced left ventricular ejection fraction and left ventricular fractional shortening, prolonged PR interval, and QT interval. These abnormalities were associated with vacuolation and increased disorder in the mitochondria of cardiomyocytes, increased protein expression levels of α‐smooth muscle actin and caspase 3, and reduced protein expression levels of Mitofusin2 (MFN2) and Sirtuin1 (SIRT1). Compared to the doxorubicin group, doxorubicin + resveratrol treatment reduced caspase 3 and manganese superoxide dismutase, and increased MFN2 and SIRT1 expression levels.

Conclusion

Doxorubicin toxicity leads to abnormal mitochondrial morphology and dysfunction in cardiomyocytes and induces apoptosis by interfering with mitochondrial fusion. Resveratrol ameliorates doxorubicin‐induced cardiotoxicity by activating SIRT1/MFN2 to improve mitochondria function.

Keywords: resveratrol, cardio‐oncology, doxorubicin‐induced cardiomyopathy, mitochondria function, SIRT1 agonists

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Received: 25 November 2022
Accepted: 08 March 2023
Published: 30 March 2023
Issue date: August 2023

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© 2023 The Authors. Tsinghua University Press.

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