S-nitrosylation-mediated coupling of G-protein alpha-2 with CXCR5 induces Hippo/YAP-dependent diabetes-accelerated atherosclerosis.

Autor: Chao ML; Key Laboratory of Cardiovascular and Cerebrovascular Medicine, Nanjing Medical University, Nanjing, China., Luo S; Key Laboratory of Cardiovascular and Cerebrovascular Medicine, Nanjing Medical University, Nanjing, China., Zhang C; Key Laboratory of Cardiovascular and Cerebrovascular Medicine, Nanjing Medical University, Nanjing, China., Zhou X; Key Laboratory of Cardiovascular and Cerebrovascular Medicine, Nanjing Medical University, Nanjing, China., Zhou M; Key Laboratory of Cardiovascular and Cerebrovascular Medicine, Nanjing Medical University, Nanjing, China., Wang J; Key Laboratory Experimental Teratology of the Ministry of Education and Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Cheeloo college of Medicine, Shandong University, Jinan, Shandong, China., Kong C; Key Laboratory of Cardiovascular and Cerebrovascular Medicine, Nanjing Medical University, Nanjing, China., Chen J; Key Laboratory of Cardiovascular and Cerebrovascular Medicine, Nanjing Medical University, Nanjing, China., Lin Z; Key Laboratory of Cardiovascular and Cerebrovascular Medicine, Nanjing Medical University, Nanjing, China., Tang X; Key Laboratory of Cardiovascular and Cerebrovascular Medicine, Nanjing Medical University, Nanjing, China., Sun S; Key Laboratory of Cardiovascular and Cerebrovascular Medicine, Nanjing Medical University, Nanjing, China., Tang X; Department of Thoracic and Cardiovascular Surgery, The Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing, China.; Nanjing Medical University Drum Tower Clinical Medical College, Nanjing, China., Chen H; Key Laboratory of Cardiovascular and Cerebrovascular Medicine, Nanjing Medical University, Nanjing, China., Wang H; The Center for Metabolic Disease Research, Temple University Lewis Katz School of Medicine, Philadelphia, PA, USA., Wang D; Department of Thoracic and Cardiovascular Surgery, The Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing, China.; Nanjing Medical University Drum Tower Clinical Medical College, Nanjing, China., Sun JP; Key Laboratory Experimental Teratology of the Ministry of Education and Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Cheeloo college of Medicine, Shandong University, Jinan, Shandong, China.; Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Peking University, Key Laboratory of Molecular Cardiovascular Science, Ministry of Education, Beijing, China., Han Y; Department of Geriatrics, First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, China. hanyi@jsph.org.cn., Xie L; Key Laboratory of Cardiovascular and Cerebrovascular Medicine, Nanjing Medical University, Nanjing, China. lipingxie@njmu.edu.cn.; Key Laboratory of Targeted Intervention of Cardiovascular Disease, Collaborative Innovation Center for Cardiovascular Disease Translational Medicine, Nanjing Medical University, Nanjing, China. lipingxie@njmu.edu.cn., Ji Y; Key Laboratory of Cardiovascular and Cerebrovascular Medicine, Nanjing Medical University, Nanjing, China. yongji@njmu.edu.cn.; Key Laboratory of Targeted Intervention of Cardiovascular Disease, Collaborative Innovation Center for Cardiovascular Disease Translational Medicine, Nanjing Medical University, Nanjing, China. yongji@njmu.edu.cn.; State Key Laboratory of Reproductive Medicine, Nanjing Medical University, Nanjing, China. yongji@njmu.edu.cn.
Jazyk: angličtina
Zdroj: Nature communications [Nat Commun] 2021 Jul 22; Vol. 12 (1), pp. 4452. Date of Electronic Publication: 2021 Jul 22.
DOI: 10.1038/s41467-021-24736-y
Abstrakt: 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.
(© 2021. The Author(s).)
Databáze: MEDLINE
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