Epigenetic Metabolic Reprogramming of Right Ventricular Fibroblasts in Pulmonary Arterial Hypertension

作者：Lian Tian, Danchen Wu, Asish Dasgupta, Kuang‐Hueih Chen, Jeffrey D. Mewburn, François Potus, Patricia D.A. Lima, Zhigang Hong, Yuan-Yuan Zhao, Charles C.T. Hindmarch, Shelby Kutty, Steeve Provencher, Sébastien Bonnet, Gopinath Sutendra, Stephen L. Archer · 发表于：Circulation Research · 年份：2020 · DOI：10.1161/circresaha.120.316443 · 被引用次数：178 · 研究领域：Pulmonary Hypertension Research and Treatments、Cardiac Fibrosis and Remodeling、Cardiovascular Function and Risk Factors

RATIONALE: Right ventricular (RV) fibrosis in pulmonary arterial hypertension contributes to RV failure. While RV fibrosis reflects changes in the function of resident RV fibroblasts (RVfib), these cells are understudied. OBJECTIVE: Examine the role of mitochondrial metabolism of RVfib in RV fibrosis in human and experimental pulmonary arterial hypertension. METHODS AND RESULTS: Male Sprague-Dawley rats received monocrotaline (MCT; 60 mg/kg) or saline. Drinking water containing no supplement or the PDK (pyruvate dehydrogenase kinase) inhibitor dichloroacetate was started 7 days post-MCT. At week 4, treadmill testing, echocardiography, and right heart catheterization were performed. The effects of PDK activation on mitochondrial dynamics and metabolism, RVfib proliferation, and collagen production were studied in RVfib in cell culture. Epigenetic mechanisms for persistence of the profibrotic RVfib phenotype in culture were evaluated. PDK expression was also studied in the RVfib of patients with decompensated RV failure (n=11) versus control (n=7). MCT rats developed pulmonary arterial hypertension, RV fibrosis, and RV failure. MCT-RVfib (but not left ventricular fibroblasts) displayed excess mitochondrial fission and had increased expression of PDK isoforms 1 and 3 that persisted for >5 passages in culture. PDK-mediated decreases in pyruvate dehydrogenase activity and oxygen consumption rate were reversed by dichloroacetate (in RVfib and in vivo) or siRNA targeting PDK 1 and 3...