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ATF4 Protects the Heart From Failure by Antagonizing Oxidative Stress

ATF4 氧化应激 线粒体 细胞生物学 生物 综合应力响应 心力衰竭 转录因子 压力过载 转录组 生物化学 化学 内分泌学 内科学 医学 基因表达 肌肉肥大 信使核糖核酸 翻译(生物学) 基因 心肌肥大
作者
Xiaoding Wang,Guangyu Zhang,Subhajit Dasgupta,Erica L Niewold,Chao Li,Qinfeng Li,Xiang Luo,Lin Tan,Anwarul Ferdous,Philip L. Lorenzi,Beverly A. Rothermel,Thomas G. Gillette,Christopher M. Adams,Philipp E. Scherer,Joseph A. Hill,Zhao V. Wang
出处
期刊:Circulation Research [Ovid Technologies (Wolters Kluwer)]
卷期号:131 (1): 91-105 被引量:17
标识
DOI:10.1161/circresaha.122.321050
摘要

Background: Cellular redox control is maintained by generation of reactive oxygen/nitrogen species balanced by activation of antioxidative pathways. Disruption of redox balance leads to oxidative stress, a central causative event in numerous diseases including heart failure. Redox control in the heart exposed to hemodynamic stress, however, remains to be fully elucidated. Methods: Pressure overload was triggered by transverse aortic constriction in mice. Transcriptomic and metabolomic regulations were evaluated by RNA-sequencing and metabolomics, respectively. Stable isotope tracer labeling experiments were conducted to determine metabolic flux in vitro. Neonatal rat ventricular myocytes and H9c2 cells were used to examine molecular mechanisms. Results: We show that production of cardiomyocyte NADPH, a key factor in redox regulation, is decreased in pressure overload-induced heart failure. As a consequence, the level of reduced glutathione is downregulated, a change associated with fibrosis and cardiomyopathy. We report that the pentose phosphate pathway and mitochondrial serine/glycine/folate metabolic signaling, 2 NADPH-generating pathways in the cytosol and mitochondria, respectively, are induced by transverse aortic constriction. We identify ATF4 (activating transcription factor 4) as an upstream transcription factor controlling the expression of multiple enzymes in these 2 pathways. Consistently, joint pathway analysis of transcriptomic and metabolomic data reveal that ATF4 preferably controls oxidative stress and redox-related pathways. Overexpression of ATF4 in neonatal rat ventricular myocytes increases NADPH-producing enzymes‚ whereas silencing of ATF4 decreases their expression. Further, stable isotope tracer experiments reveal that ATF4 overexpression augments metabolic flux within these 2 pathways. In vivo, cardiomyocyte-specific deletion of ATF4 exacerbates cardiomyopathy in the setting of transverse aortic constriction and accelerates heart failure development, attributable, at least in part, to an inability to increase the expression of NADPH-generating enzymes. Conclusions: Our findings reveal that ATF4 plays a critical role in the heart under conditions of hemodynamic stress by governing both cytosolic and mitochondrial production of NADPH.
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