心脏纤维化
医学
线粒体分裂
基因亚型
细胞生物学
线粒体
心肌细胞
巴基斯坦卢比
丙酮酸激酶
心脏功能不全
纤维化
糖酵解
丙酮酸脱氢酶激酶
激酶
心功能曲线
药理学
丙酮酸脱氢酶复合物
心肌细胞
心肌肥大
蛋白激酶A
心肌
线粒体DNA
生物化学
新陈代谢
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
出处
期刊:Circulation
[Lippincott Williams & Wilkins]
日期:2025-12-10
卷期号:153 (5): 338-357
被引量:2
标识
DOI:10.1161/circulationaha.125.075903
摘要
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 activity and tetramerization of PKM2, and cardiac fibroblast-specific PKM2 knockout aggravated cardiac fibrosis, whereas cardiac fibroblast-specific PKM2 knockout mice transfected with SNO-resistant mutant rather than wild-type PKM2 had cardiac function. Mechanistically, SNO-PKM2 drove excessive mitochondrial fission and mitochondrial dysfunction through interfering with its interaction with actin regulatory protein gelsolin. TEPP-46, a pharmacological PKM2 activator, alleviated mitochondrial fission and cardiac fibrosis. Moreover, the US Food and Drug Administration-approved drug mitapivat showed preventive and therapeutical effects on cardiac fibrosis through activating PKM2. CONCLUSIONS: SNO-PKM2 specifically increases in cardiac fibroblasts and activated cardiac fibroblasts by inducing excessive mitochondrial fission through a gelsolin-dependent manner. Mitapivat is a potential therapeutic option for attenuating cardiac fibrosis.
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