S-Nitrosylation of Pyruvate Kinase Isoform 2 Drives Cardiac Fibrosis by Promoting Mitochondrial Fission

作者：Shanshan Luo, Danyu Ye, Yan Zhang, Yan Zhang, Yu Wang, Miao Zhou, Mengqi Lv, X. Wang, Ke Zhong, Yuxiao Zhang, Yuxiao Zhang, Lulu Hu, Shan-zhen Sun, Zhi‐Ren Zhang, Bo Yu, Changhao Sun, Xiangqing Kong, Zhengrong Huang, Xin Chen, Yi Han, Liping Xie, Yong Ji · 发表于：Circulation · 年份：2025 · DOI：10.1161/circulationaha.125.075903 · 被引用次数：9 · 研究领域：Cardiac Fibrosis and Remodeling、Cardiovascular Function and Risk Factors、Congenital heart defects research

BACKGROUND: Cardiac fibrosis is a major determinant of adverse clinical outcomes of many heart diseases; currently, therapeutic strategy directly targeting fibroblasts is lacking. Nitric oxide-mediated nitrosative stress is associated with cardiac injury, and excessive nitric oxide can trigger S-nitrosylation (SNO) to specific cysteine thiol. This study aims to investigate the role of SNO in cardiac fibrosis and to identify potential therapeutic target. METHODS: SNO proteomic analysis was performed in cardiac tissue isolated from both mice subjected to transverse aortic constriction and spontaneous hypertensive rats. Elevated SNO of pyruvate kinase M2 (PKM2) was identified in cardiac fibroblasts, which was merely detected in cardiomyocytes. Cardiac fibroblast-specific PKM2 knockout mice and mice transfected with wild-type or SNO-resistant PKM2 mutant were used to determine the involvement of SNO of PKM2 (SNO-PKM2) in cardiac fibrosis. Unbiased proteomics and coimmunoprecipitation combined with mass spectrometry analysis were conducted to explore effectors mediating SNO-PKM2-induced activation of cardiac fibroblasts. A recently approved drug for rare blood disorder, mitapivat, was shown to dose-dependently relieve cardiac fibrosis. RESULTS: SNO of PKM2 at cysteine 49 and 326 increased in the heart tissue of patients with heart failure, heart tissue of murine cardiac fibrosis models, and cardiac fibroblasts stimulated with angiotensin II. SNO-PKM2 reduced pyruvate kinase activi...