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

• Published in: Nature communications Vol. 12; no. 1; pp. 4452 - 17
• Main Authors: Chao, Meng-Lin, Luo, Shanshan, Zhang, Chao, Zhou, Xuechun, Zhou, Miao, Wang, Junyan, Kong, Chuiyu, Chen, Jiyu, Lin, Zhe, Tang, Xin, Sun, Shixiu, Tang, Xinlong, Chen, Hongshan, Wang, Hong, Wang, Dongjin, Sun, Jin-Peng, Han, Yi, Xie, Liping, Ji, Yong
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 22.07.2021; Nature Publishing Group; Nature Portfolio
• Subjects: 13/109; 13/51; 14/33; 38/35; 38/39; 38/89; 38/91; 631/80/458/2386; 631/92/612/194; 64/60; 692/699/75/593/2100; 82/1; 82/58; Arteriosclerosis; Atherosclerosis; Cardiovascular diseases; Coronary artery; Coupling; CXCR5 protein; Diabetes; Diabetes mellitus; Endothelial cells; Endothelium; Guanine; Guanine nucleotide-binding protein; Humanities and Social Sciences; Inflammation; Inflammatory response; Kinases; Melatonin; multidisciplinary; Nuclear transport; Nucleotides; Patients; Protein G; Proteins; Science; Science (multidisciplinary); Translocation; Yes-associated protein
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-021-24736-y

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. S-nitrosylation can influence many pathophysiological processes. Here the authors show that the coupling efficiency of GNAI2 with CXCR5 is enhanced by S-nitrosylation of GNAI2, leading to Hippo-YAP dysfunction in endothelium, and plays a role in diabetes-accelerated atherosclerosis.