LARP6 Promotes Features of Plaque Stability and Smooth Muscle Cell Survival in Atherosclerosis

Abstract

IntroductionAcute plaque rupture or erosion followed by luminal thrombosis is a major cause of myocardial infarction and sudden cardiac death. Vulnerable plaques are characterized by a thin fibrous cap and reduced numbers of smooth muscle cells (SMCs). SMCs are essential for plaque stability, as they synthesize collagen and support fibrous cap structure. Our previous work demonstrated that insulin-like growth factor-1(IGF-1) enhances plaque stability and upregulates La ribonucleoprotein domain family member 6 (Larp6), a collagen mRNA-binding protein in SMCs. However, the specific role of Larp6 in atherosclerotic plaque stability remains undefined. MethodsIn vitro, human aortic SMCs (hAoSMCs) were used to investigate the molecular mechanism underlying IGF-1 regulation of LARP6. Using the Myh11 promotor we generated SMC specific Larp6 overexpression mice on an ApoE-/- background (SMC-Larp6) to assess effects on plaque stability. Bulk RNA sequencing data from human atherosclerotic plaques (GSE120521) were analyzed to compare stable and vulnerable plaques. ResultsIGF-1 regulates LARP6 through phosphorylation and downregulation of microRNAs. Plaques from SMC-Larp6 mice exhibited a significantly higher collagen content, accompanied by a thicker fibrous cap and a smaller necrotic core, increased presence of SMCs, without changes in overall plaque burden compared to controls. LARP6 overexpression in hAoSMCs significantly increased cell proliferation and survival under oxidative stress and promoted collagen accumulation by enhancing collagen synthesis. RNA sequencing analysis of human atherosclerotic plaques revealed reduced expression of LARP6 and downregulation of extracellular matrix-related pathways in unstable plaques, underscoring the clinical relevance of these findings. ConclusionsLarp6 overexpression promotes SMC survival, collagen synthesis and features of plaque stability under atherosclerotic conditions. These findings suggest that Larp6 is a potential therapeutic target for stabilization of atherosclerotic plaques.