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

Meng-Lin Chao, Shanshan Luo, Chao Zhang, Xuechun Zhou, Miao Zhou, Junyan Wang, Chuiyu Kong, Jiyu Chen, Zhe Lin, Xin Tang, Shixiu Sun, Xinlong Tang, Hongshan Chen, Hong Wang, Dongjin Wang, Jin-Peng Sun, Yi Han (), Liping Xie () and Yong Ji ()
Additional contact information
Meng-Lin Chao: Nanjing Medical University
Shanshan Luo: Nanjing Medical University
Chao Zhang: Nanjing Medical University
Xuechun Zhou: Nanjing Medical University
Miao Zhou: Nanjing Medical University
Junyan Wang: Shandong University
Chuiyu Kong: Nanjing Medical University
Jiyu Chen: Nanjing Medical University
Zhe Lin: Nanjing Medical University
Xin Tang: Nanjing Medical University
Shixiu Sun: Nanjing Medical University
Xinlong Tang: The Affiliated Drum Tower Hospital of Nanjing University Medical School
Hongshan Chen: Nanjing Medical University
Hong Wang: Temple University Lewis Katz School of Medicine
Dongjin Wang: The Affiliated Drum Tower Hospital of Nanjing University Medical School
Jin-Peng Sun: Shandong University
Yi Han: First Affiliated Hospital of Nanjing Medical University
Liping Xie: Nanjing Medical University
Yong Ji: Nanjing Medical University

Nature Communications, 2021, vol. 12, issue 1, 1-17

Abstract: 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.

Date: 2021
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DOI: 10.1038/s41467-021-24736-y

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