Meteorin-like protein attenuates doxorubicin-induced cardiotoxicity via activating cAMP/PKA/SIRT1 pathway
Can Hu,
Xin Zhang,
Peng Song,
Yu-Pei Yuan,
Chun-Yan Kong,
Hai-Ming Wu,
Si-Chi Xu,
Zhen-Guo Ma,
Qi-Zhu Tang
Affiliations
Can Hu
Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan 430060, China; Hubei Key Laboratory of Metabolic and Chronic Diseases, Wuhan 430060, China
Xin Zhang
Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan 430060, China; Hubei Key Laboratory of Metabolic and Chronic Diseases, Wuhan 430060, China
Peng Song
Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan 430060, China; Hubei Key Laboratory of Metabolic and Chronic Diseases, Wuhan 430060, China
Yu-Pei Yuan
Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan 430060, China; Hubei Key Laboratory of Metabolic and Chronic Diseases, Wuhan 430060, China
Chun-Yan Kong
Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan 430060, China; Hubei Key Laboratory of Metabolic and Chronic Diseases, Wuhan 430060, China
Hai-Ming Wu
Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan 430060, China; Hubei Key Laboratory of Metabolic and Chronic Diseases, Wuhan 430060, China
Si-Chi Xu
Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan 430060, China; Hubei Key Laboratory of Metabolic and Chronic Diseases, Wuhan 430060, China
Zhen-Guo Ma
Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan 430060, China; Hubei Key Laboratory of Metabolic and Chronic Diseases, Wuhan 430060, China; Corresponding author. Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan 430060, China.
Qi-Zhu Tang
Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan 430060, China; Hubei Key Laboratory of Metabolic and Chronic Diseases, Wuhan 430060, China; Corresponding author. Department of Cardiology, Renmin Hospital of Wuhan University, Hubei Key Laboratory of Metabolic and Chronic Diseases, Wuhan University at Jiefang Road 238, Wuhan 430060, PR China..
Meteorin-like (METRNL) protein is a newly identified myokine that functions to modulate energy expenditure and inflammation in adipose tissue. Herein, we aim to investigate the potential role and molecular basis of METRNL in doxorubicin (DOX)-induced cardiotoxicity. METRNL was found to be abundantly expressed in cardiac muscle under physiological conditions that was decreased upon DOX exposure. Cardiac-specific overexpression of METRNL by adeno-associated virus serotype 9 markedly improved oxidative stress, apoptosis, cardiac dysfunction and survival status in DOX-treated mice. Conversely, knocking down endogenous METRNL by an intramyocardial injection of adenovirus exacerbated DOX-induced cardiotoxicity and death. Meanwhile, METRNL overexpression attenuated, while METRNL silence promoted oxidative damage and apoptosis in DOX-treated H9C2 cells. Systemic METRNL depletion by a neutralizing antibody aggravated DOX-related cardiac injury and dysfunction in vivo, which were notably alleviated by METRNL overexpression within the cardiomyocytes. Besides, we detected robust METRNL secretion from isolated rodent hearts and cardiomyocytes, but to a less extent in those with DOX treatment. And the beneficial effects of METRNL in H9C2 cells disappeared after the incubation with a METRNL neutralizing antibody. Mechanistically, METRNL activated SIRT1 via the cAMP/PKA pathway, and its antioxidant and antiapoptotic capacities were blocked by SIRT1 deficiency. More importantly, METRNL did not affect the tumor-killing action of DOX in 4T1 breast cancer cells and tumor-bearing mice. Collectively, cardiac-derived METRNL activates SIRT1 via cAMP/PKA signaling axis in an autocrine manner, which ultimately improves DOX-elicited oxidative stress, apoptosis and cardiac dysfunction. Targeting METRNL may provide a novel therapeutic strategy for the prevention of DOX-associated cardiotoxicity.
