FCCC LOGO Faculty Publications
Chao ML , Luo S , Zhang C , Zhou X , Zhou M , Wang J , Kong C , Chen J , Lin Z , Tang X , Sun S , Tang X , Chen H , Wang H , Wang D , Sun JP , Han Y , Xie L , Ji Y
S-nitrosylation-mediated coupling of G-protein alpha-2 with CXCR5 induces Hippo/YAP-dependent diabetes-accelerated atherosclerosis
Nat Commun. 2021 Jul 22;12(1) :4452
PMID: 34294713    PMCID: PMC8298471    URL: https://www.ncbi.nlm.nih.gov/pubmed/34294713
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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.
2041-1723 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 Orcid: 0000-0002-2334-5779 Xie, Liping Orcid: 0000-0001-6440-0239 Ji, Yong Orcid: 0000-0003-2650-5747 Journal Article Research Support, Non-U.S. Gov't England Nat Commun. 2021 Jul 22;12(1):4452. doi: 10.1038/s41467-021-24736-y.