Myeloid GPSM1 regulates atherosclerosis progression by governing monocyte and macrophage chemotaxis.

The priming of blood monocytes and the infiltration of monocyte-derived macrophages into the vessel walls are the central part of atherosclerosis. However, the mechanisms underlying the processes remain unclear. Here we report that G-protein-signaling modulator 1 (GPSM1) plays a critical role in atherogenesis. We found that GPSM1 expression in lesional macrophages was increased during atherosclerosis development both in mice and human. Myeloid-specific GPSM1 ablation protects mice against atherosclerosis and reduces aortic inflammation, in both Apoe-/- mice and an AAV-PCSK9 injection model. Conversely, myeloid-restricted overexpression of GPSM1 accelerates aortic inflammation and promotes atherosclerosis development in mice. Mechanistically, GPSM1 deficiency suppressed monocyte priming including chemotaxis and adhesion through inhibition of p38/ERK MAPK pathway regulated by cAMP/PKA/KLF4/PMP22 axis, thereby alleviating pro-inflammatory responses within atherosclerotic plaques. Blockade of PMP22 using siRNA-loaded liposomes protected GPSM1 overexpression mice from atherosclerosis. Furthermore, a small-molecule compound inhibiting GPSM1 function could suppress atherosclerosis in vivo. In conclusion, our findings establish that GPSM1 is a novel regulator of atherosclerosis development and targeting GPSM1 might be a promising therapy against atherosclerosis. Overall design: To understand how GPSM1 affects macrophage chemotaxis, we performed RNA-Seq transcriptomic analysis on GPSM1fl/fl versus GPSM1LKO BMDMs upon CCL2 stimulation.