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

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.