Voltage-dependent anion channel 1 (VDAC1) overexpression alleviates cardiac fibroblast activation in cardiac fibrosis via regulating fatty acid metabolism
Geer Tian,
Junteng Zhou,
Yue Quan,
Qihang Kong,
Junli Li,
Yanguo Xin,
Wenchao Wu,
Xiaoqiang Tang,
Xiaojing Liu
Affiliations
Geer Tian
Department of Cardiology and Laboratory of Cardiovascular Diseases, West China Hospital, Sichuan University, Chengdu, 610041, PR China
Junteng Zhou
Health Management Center, General Practice Medical Center, West China Hospital, Sichuan University, Chengdu, 610041, China
Yue Quan
Department of Cardiology and Laboratory of Cardiovascular Diseases, West China Hospital, Sichuan University, Chengdu, 610041, PR China
Qihang Kong
Department of Cardiology and Laboratory of Cardiovascular Diseases, West China Hospital, Sichuan University, Chengdu, 610041, PR China
Junli Li
Department of Cardiology and Laboratory of Cardiovascular Diseases, West China Hospital, Sichuan University, Chengdu, 610041, PR China
Yanguo Xin
Department of Cardiology and Laboratory of Cardiovascular Diseases, West China Hospital, Sichuan University, Chengdu, 610041, PR China
Wenchao Wu
Department of Cardiology and Laboratory of Cardiovascular Diseases, West China Hospital, Sichuan University, Chengdu, 610041, PR China
Xiaoqiang Tang
Key Laboratory of Birth Defects and Related Diseases of Women and Children of MOE, State Key Laboratory of Biotherapy, West China Second University Hospital, Sichuan University, No.17 People's South Road, Chengdu, Sichuan, 610041, China; National Health Commission Key Laboratory of Chronobiology, Sichuan University, No.17 People's South Road, Chengdu, Sichuan, 610041, China; Development and Related Diseases of Women and Children, Key Laboratory of Sichuan Province, West China Second University Hospital, Sichuan University, No.17 People's South Road, Chengdu, Sichuan, 610041, China; Corresponding author. Key Laboratory of Birth Defects and Related Diseases of Women and Children of MOE, State Key Laboratory of Biotherapy, West China Second University Hospital, Sichuan University, No.17 People's South Road, Chengdu, Sichuan, 610041, PR China.
Xiaojing Liu
Department of Cardiology and Laboratory of Cardiovascular Diseases, West China Hospital, Sichuan University, Chengdu, 610041, PR China; Corresponding author. Laboratory of Cardiovascular Diseases, West China Hospital, Sichuan University, Chengdu, Sichuan Province, 610041, PR China.
Cardiac fibrosis is characterized by the excessive deposition of extracellular matrix in the myocardium with cardiac fibroblast activation, leading to chronic cardiac remodeling and dysfunction. However, little is known about metabolic alterations in fibroblasts during cardiac fibrosis, and there is a lack of pharmaceutical treatments that target metabolic dysregulation. Here, we provided evidence that fatty acid β-oxidation (FAO) dysregulation contributes to fibroblast activation and cardiac fibrosis. With transcriptome, metabolome, and functional assays, we demonstrated that FAO was downregulated during fibroblast activation and cardiac fibrosis, and that perturbation of FAO reversely affected the fibroblast-to-myofibroblast transition. The decrease in FAO may be attributed to reduced long-chain fatty acid (LCFA) uptake. Voltage-dependent anion channel 1 (VDAC1), the main gatekeeper of the outer mitochondrial membrane (OMM), serves as the transporter of LCFA into the mitochondria for further utilization and has been shown to be decreased in myofibroblasts. In vitro, the addition of exogenous VDAC1 was shown to ameliorate cardiac fibroblast activation initiated by transforming growth factor beta 1 (TGF-β1) stimuli, and silencing of VDAC1 displayed the opposite effect. A mechanistic study revealed that VDAC1 exerts a protective effect by regulating LCFA uptake into the mitochondria, which is impaired by an inhibitor of carnitine palmitoyltransferase 1A. In vivo, AAV9-mediated overexpression of VDAC1 in myofibroblasts significantly alleviated transverse aortic constriction (TAC)-induced cardiac fibrosis and rescued cardiac function in mice. Finally, we treated mice with the VDAC1-derived R-Tf-D-LP4 peptide, and the results showed that R-Tf-D-LP4 prevented TAC-induced cardiac fibrosis and dysfunction in mice. In conclusion, this study provides evidence that VDAC1 maintains FAO metabolism in cardiac fibroblasts to repress fibroblast activation and cardiac fibrosis and suggests that the VDAC1 peptide is a promising drug for rescuing fibroblast metabolism and repressing cardiac fibrosis.
