Introduction & Objective: The infiltration of macrophages into the vessel walls are the central part of atherosclerosis-one kind of macrovascular complication of diabetes. However, the detailed mechanisms remain unclear. We aim to determine whether myeloid cell G-protein-signaling modulator 1 (GPSM1) regulates atherosclerosis and macrophage chemotaxis.
Methods: We used myeloid-specific GPSM1 ablation mice on Apoe-/- background, and GPSM1 overexpression/deficient mice with an AAV-PCSK9 injection to explore function of GPSM1 in atherosclerosis. BMDMs and THP-1 cells were used to access mechanism of GPSM1 in regulating macrophage chemotaxis. Apoe-/- mice were injected with a small-molecule compound, AN-465 that countered GPSM1 function to evaluate potential therapeutic effects of GPSM1 on atherogenesis.
Results: Myeloid-specific GPSM1 ablation protects mice against atherosclerosis and reduces atherosclerotic plaque formation and aortic inflammation, both in Apoe-/- double knockout mice and an AAV-PCSK9 injection model. In contrast, myeloid-restricted overexpression of GPSM1 induces promotes atherosclerosis development in mice. Particularly, GPSM1 deficiency suppresses oxidized low-density lipoprotein (oxLDL)-burdened monocytes priming and macrophages chemotaxis and migration, thereby alleviating pro-inflammatory responses within atherosclerotic plaque. Mechanistically, GPSM1 loss inhibits P38/ERK MAPK pathway through cAMP/PKA/KLF4/PMP22 axis in macrophages, ultimately resulting in impaired macrophage chemotaxis and migration. Finally, pharmacological inhibition of GPSM1 with AN-465 reduces plaque formation and macrophage infiltration, suggesting that targeting GPSM1 would be an approach for the treatment of macrovascular complication of diabetes.
Conclusion: Our findings establish that GPSM1 is a new regulator of atherosclerosis and suggest GPSM1 as a potential therapeutic target for atherosclerosis.
Y. Zhang: None. C. Hu: None.
