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. 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing / metabolism
  • Animals
  • Atherosclerosis / etiology*
  • Atherosclerosis / metabolism*
  • Cells, Cultured
  • Cysteine / chemistry
  • Diabetes Mellitus, Experimental / complications
  • Diabetes Mellitus, Experimental / metabolism
  • Diabetic Angiopathies / etiology*
  • Diabetic Angiopathies / metabolism*
  • GTP-Binding Protein alpha Subunit, Gi2 / chemistry
  • GTP-Binding Protein alpha Subunit, Gi2 / genetics
  • GTP-Binding Protein alpha Subunit, Gi2 / metabolism*
  • Human Umbilical Vein Endothelial Cells
  • Humans
  • Male
  • Melatonin / pharmacology
  • Mice
  • Mice, Knockout
  • Mutagenesis, Site-Directed
  • Nitric Oxide Synthase Type II / metabolism
  • Nitroso Compounds / chemistry
  • Nitroso Compounds / metabolism
  • Protein-Serine-Threonine Kinases / metabolism
  • Receptors, CXCR5 / deficiency
  • Receptors, CXCR5 / genetics
  • Receptors, CXCR5 / metabolism
  • Transcription Factors / metabolism


  • Adaptor Proteins, Signal Transducing
  • CXCR5 protein, human
  • CXCR5 protein, mouse
  • Nitroso Compounds
  • Receptors, CXCR5
  • Transcription Factors
  • YAP1 protein, human
  • Yap1 protein, mouse
  • NOS2 protein, human
  • Nitric Oxide Synthase Type II
  • Nos2 protein, mouse
  • Hippo protein, human
  • Hippo protein, mouse
  • Protein-Serine-Threonine Kinases
  • GNAI2 protein, human
  • GTP-Binding Protein alpha Subunit, Gi2
  • Gnai2 protein, mouse
  • Melatonin
  • Cysteine