Skeletal Muscle SIRT3 Deficiency Contributes to Pulmonary Vascular Remodeling in Pulmonary Hypertension Due to Heart Failure With Preserved Ejection Fraction

作者：Jia-Rong Jheng, Yang Bai, Kentaro Noda, Joshua R. Huot, Todd Cook, Amanda Fisher, Yi-Yun Chen, Dmitry A. Goncharov, Elena A. Goncharova, Marc A. Simon, Yingze Zhang, Daniel E. Forman, Mauricio Rojas, Roberto F. Machado, Johan Auwerx, Mark T. Gladwin, Yen‐Chun Lai · 发表于：Circulation · 年份：2024 · DOI：10.1161/circulationaha.124.068624 · 被引用次数：24 · 研究领域：Pulmonary Hypertension Research and Treatments、Sirtuins and Resveratrol in Medicine、Cardiovascular Function and Risk Factors

BACKGROUND: Pulmonary hypertension (PH) is a major complication linked to adverse outcomes in heart failure with preserved ejection fraction (HFpEF), yet no specific therapies exist for PH associated with HFpEF (PH-HFpEF). We have recently reported on the role of skeletal muscle SIRT3 (sirtuin-3) in modulation of PH-HFpEF, suggesting a novel endocrine signaling pathway for skeletal muscle modulation of pulmonary vascular remodeling. METHODS: Using skeletal muscle-specific Sirt3 knockout mice ( Sirt3 skm-/- ) and mass spectrometry-based comparative secretome analysis, we attempted to define the processes by which skeletal muscle SIRT3 defects affect pulmonary vascular health in PH-HFpEF. RESULTS: Sirt3 skm-/- mice exhibited reduced pulmonary vascular density accompanied by pulmonary vascular proliferative remodeling and elevated pulmonary pressures. Comparative analysis of secretome by mass spectrometry revealed elevated secretion levels of LOXL2 (lysyl oxidase homolog 2) in SIRT3-deficient skeletal muscle cells. Elevated circulation and protein expression levels of LOXL2 were also observed in plasma and skeletal muscle of Sirt3 skm-/- mice, a rat model of PH-HFpEF, and humans with PH-HFpEF. In addition, expression levels of CNPY2 (canopy fibroblast growth factor signaling regulator 2), a known proliferative and angiogenic factor, were increased in pulmonary artery endothelial cells and pulmonary artery smooth muscle cells of Sirt3 skm-/- mice and animal models of PH-HFpEF. CN...