Voltage-dependent anion channel 1 (VDAC1) overexpression alleviates cardiac fibroblast activation in cardiac fibrosis via regulating fatty acid metabolism

作者：Geer Tian, Junteng Zhou, Yue Quan, Qihang Kong, Junli Li, Yanguo Xin, Wenchao Wu, Xiaoqiang Tang, Xiaojing Liu · 发表于：Redox Biology · 年份：2023 · DOI：10.1016/j.redox.2023.102907 · 被引用次数：25 · 研究领域：Cardiovascular Function and Risk Factors、Mitochondrial Function and Pathology、Peroxisome Proliferator-Activated Receptors

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...