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. To understand how GPSM1 affects macrophage chemotaxis, we performed RNA-Seq transcriptomic analysis on GPSM1fl/fl versus GPSM1LKO BMDMs upon CCL2 stimulation.

血液单核细胞致敏及单核细胞衍生巨噬细胞向血管壁浸润是动脉粥样硬化（atherosclerosis）发生发展的核心环节。然而，该过程的潜在分子机制仍未阐明。本研究证实G蛋白信号调节因子1（G-protein-signaling modulator 1，GPSM1）在动脉粥样硬化发生中发挥关键作用。我们发现，在小鼠与人类的动脉粥样硬化进程中，病变区域巨噬细胞内的GPSM1表达水平均显著上调。髓系特异性GPSM1敲除可在载脂蛋白E基因敲除（Apoe-/-）小鼠及腺相关病毒-前蛋白转化酶枯草溶菌素9（AAV-PCSK9）注射模型中，保护小鼠抵御动脉粥样硬化并减轻主动脉炎症。反之，髓系限制性GPSM1过表达则会加剧小鼠主动脉炎症并促进动脉粥样硬化进展。从机制层面来看，GPSM1缺失可通过抑制由环磷酸腺苷（cyclic adenosine monophosphate，cAMP）/蛋白激酶A（protein kinase A，PKA）/Kruppel样因子4（Kruppel-like factor 4，KLF4）/周围髓鞘蛋白22（peripheral myelin protein 22，PMP22）轴调控的p38/细胞外调节蛋白激酶丝裂原活化蛋白激酶（p38/ERK MAPK）通路，抑制单核细胞致敏（包括趋化与黏附过程），从而减轻动脉粥样硬化斑块内的促炎反应。使用负载小干扰RNA（small interfering RNA，siRNA）的脂质体阻断PMP22，可使GPSM1过表达小鼠免受动脉粥样硬化侵害。此外，一种可抑制GPSM1功能的小分子化合物在体内可延缓动脉粥样硬化进展。综上，本研究结果证实GPSM1是动脉粥样硬化进展的新型调控因子，靶向GPSM1或可成为治疗动脉粥样硬化的潜在策略。为阐明GPSM1如何影响巨噬细胞趋化，我们在CC趋化因子配体2（C-C motif chemokine ligand 2，CCL2）刺激下，对GPSM1 flox/flox（GPSM1fl/fl）与髓系特异性GPSM1敲除（GPSM1LKO）小鼠的骨髓来源巨噬细胞（bone marrow-derived macrophages，BMDMs）进行了RNA测序（RNA sequencing，RNA-Seq）转录组分析。