糖尿病
S-亚硝基化
炎症
内皮功能障碍
内科学
医学
细胞生物学
内分泌学
化学
生物
半胱氨酸
生物化学
酶
作者
Meng‐Lin Chao,Shuang Luo,Chao Zhang,Xuechun Zhou,Miao Zhou,Junyan Wang,Chuiyu Kong,Jiyu Chen,Liu Zhe,Xin Tang,Shixiu Sun,Xingming Tang,Hongshan Chen,Hong Wang,Dongjin Wang,Jing Sun,Yi Han,Liping Xie,Yong Ji
标识
DOI:10.1038/s41467-021-24736-y
摘要
Abstract Atherosclerosis-associated cardiovascular disease is one of the main causes of death and disability among patients with diabetes mellitus. However, little is known about the impact of S-nitrosylation in diabetes-accelerated atherosclerosis. Here, we show increased levels of S-nitrosylation of guanine nucleotide-binding protein G(i) subunit alpha-2 (SNO-GNAI2) at Cysteine 66 in coronary artery samples from diabetic patients with atherosclerosis, consistently with results from mice. Mechanistically, SNO-GNAI2 acted by coupling with CXCR5 to dephosphorylate the Hippo pathway kinase LATS1, thereby leading to nuclear translocation of YAP and promoting an inflammatory response in endothelial cells. Furthermore, Cys-mutant GNAI2 refractory to S-nitrosylation abrogated GNAI2-CXCR5 coupling, alleviated atherosclerosis in diabetic mice, restored Hippo activity, and reduced endothelial inflammation. In addition, we showed that melatonin treatment restored endothelial function and protected against diabetes-accelerated atherosclerosis by preventing GNAI2 S-nitrosylation. In conclusion, SNO-GNAI2 drives diabetes-accelerated atherosclerosis by coupling with CXCR5 and activating YAP-dependent endothelial inflammation, and reducing SNO-GNAI2 is an efficient strategy for alleviating diabetes-accelerated atherosclerosis.
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