ATF4 Protects the Heart From Failure by Antagonizing Oxidative Stress.
ATF4 Protects the Heart From Failure by Antagonizing Oxidative Stress.
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DOI：
10.1161/circresaha.122.321050
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发表时间：
2022-06-24
影响因子：
20.1
通讯作者：
Wang, Zhao, V
中科院分区：
文献类型：
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作者：
Wang, Xiaoding;Zhang, Guangyu;Dasgupta, Subhajit;Niewold, Erica L.;Li, Chao;Li, Qinfeng;Luo, Xiang;Tan, Lin;Ferdous, Anwarul;Lorenzi, Philip L.;Rothermel, Beverly A.;Gillette, Thomas G.;Adams, Christopher M.;Scherer, Philipp E.;Hill, Joseph A.;Wang, Zhao, V
细胞氧化还原控制是通过产生活性氧/氮物质来维持的，并通过抗氧化途径的激活来平衡。氧化还原平衡的破坏会导致氧化应激，这是包括心力衰竭在内的许多疾病的核心致病事件。然而，暴露于血流动力学应激的心脏中的氧化还原控制仍有待充分阐明。压力超负荷是由小鼠横向主动脉缩窄（TAC）引发的。分别通过RNA测序和代谢组学评估转录组学和代谢组学调控。进行稳定同位素示踪标记实验以确定体外代谢通量。使用新生大鼠心室肌细胞 (NRVM) 和 H9c2 细胞来检查分子机制。我们发现，在压力超负荷引起的心力衰竭中，心肌细胞 NADPH（氧化还原调节的关键因素）的产生减少。结果，还原型谷胱甘肽的水平下调，这种变化与纤维化和心肌病相关。我们报道，戊糖磷酸途径（PPP）和线粒体丝氨酸/甘氨酸/叶酸代谢信号，分别是细胞质和线粒体中的两条 NADPH 生成途径，是由 TAC 诱导的。我们将激活转录因子 4 (ATF4) 确定为控制这两条途径中多种酶表达的上游转录因子。一致地，转录组学和代谢组学数据的联合通路分析表明，ATF4 优先控制氧化应激和氧化还原相关通路。 NRVM 中 ATF4 的过度表达会增加产生 NADPH 的酶，而 ATF4 的沉默会降低其表达。此外，稳定同位素示踪实验表明，ATF4 过度表达会增加这两条途径内的代谢通量。在体内，心肌细胞特异性缺失 ATF4 会加剧 TAC 情况下的心肌病，并加速心力衰竭的发展，这至少部分归因于无法增加 NADPH 生成酶的表达。我们的研究结果表明，ATF4 在血流动力学应激条件下通过控制细胞质和线粒体 NADPH 的产生在心脏中发挥着关键作用。
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. Pressure overload was triggered by transverse aortic constriction (TAC) 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 (NRVMs) and H9c2 cells were used to examine molecular mechanisms. 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 (PPP) and mitochondrial serine/glycine/folate metabolic signaling, two NADPH-generating pathways in the cytosol and mitochondria, respectively, are induced by TAC. We identify activating transcription factor 4 (ATF4) as an upstream transcription factor controlling the expression of multiple enzymes in these two pathways. Consistently, joint pathway analysis of transcriptomic and metabolomic data reveals that ATF4 preferably controls oxidative stress and redox-related pathways. Overexpression of ATF4 in NRVMs 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 two pathways. In vivo, cardiomyocyte specific deletion of ATF4 exacerbates cardiomyopathy in the setting of TAC and accelerates heart failure development, attributable, at least in part, to an inability to increase the expression of NADPH-generating enzymes. 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.