Endothelial Scaffolding Protein ENH (Enigma Homolog Protein) Promotes PHLPP2 (Pleckstrin Homology Domain and Leucine-Rich Repeat Protein Phosphatase 2)-Mediated Dephosphorylation of AKT1 and eNOS (Endothelial NO Synthase) Promoting Vascular Remodeling

作者：Jiaqi Huang, Changhong Cai, Tianyu Zheng, Xinyan Wu, Dongfei Wang, Kaijie Zhang, Bocheng Xu, Ruochen Yan, Hui Gong, Jie Zhang, Yueli Shi, Zhiyong Xu, Xue Zhang, Xuemin Zhang, Tao Shang, Jianhong Zhou, Xiaogang Guo, Chunlai Zeng, En Yin Lai, Changchun Xiao, Ju Chen, Shu Wan, Wen‐Hsien Liu, Yuehai Ke, Hongqiang Cheng · 发表于：Arteriosclerosis Thrombosis and Vascular Biology · 年份：2020 · DOI：10.1161/atvbaha.120.314172 · 被引用次数：34 · 研究领域：Nitric Oxide and Endothelin Effects、Mitochondrial Function and Pathology、Cancer, Hypoxia, and Metabolism

OBJECTIVE: A decrease in nitric oxide, leading to vascular smooth muscle cell proliferation, is a common pathological feature of vascular proliferative diseases. Nitric oxide synthesis by eNOS (endothelial nitric oxide synthase) is precisely regulated by protein kinases including AKT1. ENH (enigma homolog protein) is a scaffolding protein for multiple protein kinases, but whether it regulates eNOS activation and vascular remodeling remains unknown. Approach and Results: ENH was upregulated in injured mouse arteries and human atherosclerotic plaques and was associated with coronary artery disease. Neointima formation in carotid arteries, induced by ligation or wire injury, was greatly decreased in endothelium-specific ENH-knockout mice. Vascular ligation reduced AKT and eNOS phosphorylation and nitric oxide production in the endothelium of control but not ENH-knockout mice. ENH was found to interact with AKT1 and its phosphatase PHLPP2 (pleckstrin homology domain and leucine-rich repeat protein phosphatase 2). AKT and eNOS activation were prolonged in VEGF (vascular endothelial growth factor)-induced ENH- or PHLPP2-deficient endothelial cells. Inhibitors of either AKT or eNOS effectively restored ligation-induced neointima formation in ENH-knockout mice. Moreover, endothelium-specific PHLPP2-knockout mice displayed reduced ligation-induced neointima formation. Finally, PHLPP2 was increased in the endothelia of human atherosclerotic plaques and blood cells from patients with co...