Mitochondrial GSNOR Alleviates Cardiac Dysfunction via ANT1 Denitrosylation

作者：Xin Tang, Shuang Zhao, Jieqiong Liu, X. Liu, Xinqi Sha, Changgao Huang, Lulu Hu, Shixiu Sun, Yuanqing Gao, Hongshan Chen, Zhi‐Ren Zhang, Dongjin Wang, Yuexi Gu, Shao‐Liang Chen, Liansheng Wang, Aihua Gu, Feng Chen, Jun Pu, Xin Chen, Bo Yu, Liping Xie, Zhengrong Huang, Yi Han, Yong Ji · 发表于：Circulation Research · 年份：2023 · DOI：10.1161/circresaha.123.322654 · 被引用次数：53 · 研究领域：Nitric Oxide and Endothelin Effects、Cardiac Fibrosis and Remodeling、Redox biology and oxidative stress

BACKGROUND: The cardiac-protective role of GSNOR (S-nitrosoglutathione reductase) in the cytoplasm, as a denitrosylase enzyme of S-nitrosylation, has been reported in cardiac remodeling, but whether GSNOR is localized in other organelles and exerts novel effects remains unknown. We aimed to elucidate the effects of mitochondrial GSNOR, a novel subcellular localization of GSNOR, on cardiac remodeling and heart failure (HF). METHODS: GSNOR subcellular localization was observed by cellular fractionation assay, immunofluorescent staining, and colloidal gold particle staining. Overexpression of GSNOR in mitochondria was achieved by mitochondria-targeting sequence-directed adeno-associated virus 9. Cardiac-specific knockout of GSNOR mice was used to examine the role of GSNOR in HF. S-nitrosylation sites of ANT1 (adenine nucleotide translocase 1) were identified using biotin-switch and liquid chromatography-tandem mass spectrometry. RESULTS: GSNOR expression was suppressed in cardiac tissues of patients with HF. Consistently, cardiac-specific knockout mice showed aggravated pathological remodeling induced by transverse aortic constriction. We found that GSNOR is also localized in mitochondria. In the angiotensin II-induced hypertrophic cardiomyocytes, mitochondrial GSNOR levels significantly decreased along with mitochondrial functional impairment. Restoration of mitochondrial GSNOR levels in cardiac-specific knockout mice significantly improved mitochondrial function and cardiac pe...