Endothelial Matrin‐3 Limits Cellular Senescence and Lipid Dysregulation to Protect Against Murine Atherosclerosis

Abstract

ABSTRACT Matrin‐3 is a DNA‐ and RNA‐binding protein implicated in cardiovascular development. However, the role of endothelial Matrin‐3 in atherosclerosis has not been previously studied. Here, we found that Matrin‐3 silencing induces endothelial senescence, characterized by reduced cell proliferation, increased senescence‐associated β‐galactosidase activity, and impaired mitochondrial function in vitro. Quantitative proteomics and bulk RNA‐sequencing identified hundreds of differentially expressed genes and proteins in human endothelial cells. Bioinformatic analyses revealed enrichment of pathways related to DNA replication, p53 signaling, cell‐cycle regulation, and cellular senescence. To examine the role of endothelial Matrin‐3 in atherosclerosis, we generated Matrin‐3 floxed mice on a low‐density lipoprotein receptor‐knockout background and crossed them with mice carrying an endothelial cell‐specific, tamoxifen‐inducible Cre driver. In a mouse model of atherosclerosis, endothelial cell‐specific Matrin‐3 deficiency increased atherosclerotic lesion area by 1.41‐fold and was associated with increased plasma low‐density lipoprotein cholesterol and triglycerides, increased hepatic cholesterol and triglycerides, and substantial transcriptional alterations in the aortic intima. Endothelial Matrin‐3 deficiency also induced hepatic steatosis, fibrosis, inflammation, and endothelial senescence. Single‐nucleus RNA‐sequencing of the liver further revealed transcriptional reprogramming of hepatocytes, including alterations in pathways related to lipid metabolism, inflammation, and constitutive androstane receptor signaling, consistent with a functional link between endothelial Matrin‐3 deficiency and hepatocyte transcriptional responses. Finally, Matrin‐3 expression was reduced in mouse and human atherosclerotic plaques. Together, these findings identify endothelial Matrin‐3 as an important regulator of endothelial senescence and lipid homeostasis and demonstrate that endothelial Matrin‐3 deficiency is associated with both local vascular alterations and systemic metabolic dysfunction in atherosclerosis.