PLCE1 exacerbates the development of atherosclerosis by driving endothelial dysfunction and macrophage inflammation via targeting CTNNB1

The infiltration of macrophages and the inflammatory response they mediate, which are initiated by endothelial dysfunction, are pivotal in both the initiation and progression of atherogenesis. Phospholipase C epsilon 1 (PLCE1) is significantly involved in cardiovascular diseases, in part due to its regulation of vascular inflammation. This study seeks to explore the specific function of PLCE1 in the development of atherosclerosis. Bioinformatic analysis of datasets from the GEO database demonstrated abundant PLCE1 expression in patients with restenosis or myocardial infarction. Consistently, PLCE1 was upregulated in atherosclerotic plaques of high-fat diet (HFD)-fed ApoE -/- mice as well as in endothelial cells stimulated with oxidized low-density lipoprotein (OX-LDL). Additionally, double immunofluorescence staining revealed a strong co-localization of PLCE1 with the endothelium. The deficiency of PLCE1 in ApoE -/- mice mitigated endothelial dysfunction, as evidenced by reduced expression of intercellular adhesion molecule 1 (ICAM-1), vascular cell adhesion molecule 1 (VCAM-1), and various chemokines, which subsequently inhibited pro-inflammatory M1 macrophage polarization. The observed effects corresponded with decreased formation of atherosclerotic plaques and lower plaque vulnerability. Consistent results were also obtained from in vitro studies. Furthermore, bone marrow transplantation experiments suggested that the improvement in atherosclerosis was primarily due to the deletion of PLCE1 in resident vascular endothelial cells. Mechanistically, PLCE1 mediated endothelial dysfunction, macrophage infiltration, and inflammation, in part through its direct interaction with CTNNB1. These findings indicate that PLCE1 is an important regulator of vascular endothelial dysfunction, leading to a classical macrophage polarization switch through its interaction with CTNNB1, which collectively accelerates the development of atherosclerosis. Our study suggests that PLCE1 is a promising therapeutic target for the management of atherogenesis.