Endothelial MRG15 Is a Mechanosensitive Suppressor of Atherosclerosis

Disturbed blood flow induces early endothelial inflammation in atherosclerosis, yet the precise mechanisms of endothelial sensing of disturbed flow remain incompletely understood. In this study, we integrated proteomic profiling of human endothelial cells (ECs) subjected to disturbed flow with coronary artery disease risk related genes from large-scale genome-wide association studies (GWAS). We identified mortality factor 4-like protein 1 (MORF4L1, also called MRG15) as a critical modulator in the pathogenesis of atherosclerosis induced by disturbed flow. We show that the expression of MRG15 is markedly reduced in ECs of human aortic atherosclerotic plaques, as well as in ECs exposed to disturbed flow in mouse carotid artery and in cultured human umbilical vein endothelial cells (HUVECs). Endothelial-specific deletion of Mrg15 significantly worsened, while its overexpression attenuated endothelial inflammation and atherosclerotic lesions in turbulent blood flow- or Western diet-induced mouse atherosclerosis model. Single-cell transcriptomics showed that Mrg15 deficiency increased endothelial inflammation and intercellular adhesion molecule 1 (Icam1) expression, and enhanced integrin-mediated adhesion pathways. Mechanistically, MRG15 facilitated the recruitment of enhancer of zeste homolog 2 (EZH2) to maintain repressive histone H3 lysine 27 trimethylation (H3K27me3) marks on the promoters of ICAM1 and integrin subunit alpha 5 (ITGA5). Disturbed blood flow rapidly led to an elevation of protein neddylation, which subsequently induced neddylation-dependent degradation of MRG15 within endothelial cells. This degradation of MRG15 alleviated the transcriptional repression of ICAM1 and ITGA5, thereby enhancing monocyte adhesion to ECs. These findings highlight endothelial MRG15 as a mechanosensitive suppressor of atherosclerosis induced by disturbed flow. Consequently, MRG15 emerges as a promising novel therapeutic target for atherosclerosis.