CARMN loss promotes VSMC-derived foam cell formation and atherosclerosis through transcriptional downregulation of autophagy.

Vascular smooth muscle cells (VSMCs) are a significant source of foam cells in atherosclerosis, but the mechanism involved in the formation of VSMC-derived foam cells remains poorly understood. Although long noncoding RNAs (lncRNAs) are dysregulated in lipid metabolism disorder and atherosclerosis, little is known about their involvement in VSMC-derived foam cell formation. Silencing CARMN promoted lipid accumulation and VSMC-derived foam cell formation in high-fat diet-fed ApoE(-/-) mice. Furthermore, CARMN knockdown reduced cholesterol efflux and promoted VSMC-derived foam cell formation by regulating autophagy. In exploring the mechanism by which CARMN regulates autophagy, our results demonstrated that CARMN knockdown reduced autophagy in VSMCs by modulating the AKT/ATG7 pathway through transcriptional suppression of the adjacent gene casein kinase 1 alpha 1 (CSNK1A1). In vivo, CARMN deficiency led to reduced autophagy in VSMCs and increased atherosclerotic lesions, characterized by increased lipid deposition and necrotic core. Our findings reveal that CARMN plays an essential role in the regulation of VSMC autophagy, which is crucial for the formation of VSMC-derived foam cells and the progression of atherosclerosis. These results provide new insights into the molecular mechanisms underlying VSMC autophagy and suggest that CARMN is a potential therapeutic target for atherosclerosis.