Inactivation of Malic Enzyme 1 in Endothelial Cells Alleviates Pulmonary Hypertension

作者：Ya Luo, Xianmei Qi, Zhenxi Zhang, Jiawei Zhang, Bolun Li, Ting Shu, Xiaona Li, Huiyuan Hu, Jinqiu Li, Qihao Tang, Yitian Zhou, Mingyao Wang, Tianfei Fan, Wenjun Guo, Ying Liu, J. Zhang, Junling Pang, Peiran Yang, Ran Gao, Wenhui Chen, Yan Chen, Yanjiang Xing, Wenjing Du, Jing Wang, Chen Wang · 发表于：Circulation · 年份：2024 · DOI：10.1161/circulationaha.123.067579 · 被引用次数：40 · 研究领域：Pulmonary Hypertension Research and Treatments、Mitochondrial Function and Pathology、Eicosanoids and Hypertension Pharmacology

BACKGROUND: Pulmonary hypertension (PH) is a progressive cardiopulmonary disease with a high mortality rate. Although growing evidence has revealed the importance of dysregulated energetic metabolism in the pathogenesis of PH, the underlying cellular and molecular mechanisms are not fully understood. In this study, we focused on ME1 (malic enzyme 1), a key enzyme linking glycolysis to the tricarboxylic acid cycle. We aimed to determine the role and mechanistic action of ME1 in PH. METHODS: Global and endothelial-specific ME1 knockout mice were used to investigate the role of ME1 in hypoxia- and SU5416/hypoxia (SuHx)–induced PH. Small hairpin RNA and ME1 enzymatic inhibitor (ME1*) were used to study the mechanism of ME1 in pulmonary artery endothelial cells. Downstream key metabolic pathways and mediators of ME1 were identified by metabolomics analysis in vivo and ME1-mediated energetic alterations were examined by Seahorse metabolic analysis in vitro. The pharmacological effect of ME1* on PH treatment was evaluated in PH animal models induced by SuHx. RESULTS: We found that ME1 protein level and enzymatic activity were highly elevated in lung tissues of patients and mice with PH, primarily in vascular endothelial cells. Global knockout of ME1 protected mice from developing hypoxia- or SuHx-induced PH. Endothelial-specific ME1 deletion similarly attenuated pulmonary vascular remodeling and PH development in mice, suggesting a critical role of endothelial ME1 in PH. Mechanistic...