Vascular smooth muscle cell RNA-binding protein U2AF2 induces copper death by regulating C1qbp expression, delaying development of atherosclerosise.

Abstract

BACKGROUND: Atherosclerosis (AS) is the main pathological basis of atherosclerosis-related cardiovascular and cerebrovascular diseases. The phenotypic conversion and death mechanisms of vascular smooth muscle cells (VSMCs) are crucial during its development. This study reveals the molecular mechanisms of the C1qbp-DLAT axis and the U2AF2 (U2 Small Nuclear RNA Auxiliary Factor 2)-NEAT1 network in regulating cuproptosis in AS. METHODS: In this study, an ApoEmouse model was constructed by high-fat diet (HFD) induction. Cell culture, molecular biology, immunology and histology methods were employed to explore the role of the U2AF2-C1qbp-copper death regulatory axis in the development of AS. Techniques such as qRT-PCR, Western blot, immunoprecipitation, RNA pull-down and RIP were used to detect the expression of related genes and proteins and analyze their functions. RESULTS: The study revealed elevated copper ion levels and dysregulated cuproptosis-related genes in an AS model. U2AF2 stabilized C1qbp mRNA, enhancing C1qbp protein expression, which promoted DLAT oligomerization to regulate cuproptosis. LncRNA NEAT1 facilitated this process by scaffolding U2AF2-C1qbp mRNA interaction. Targeted inhibition of U2AF2 significantly improved AS pathological characteristics, reduced lipid deposition, collagen deposition and macrophage infiltration within the plaque, increased smooth muscle cell content and lowered serum levels of total cholesterol (TC), total triglyceride (TG) and low-density lipoprotein cholesterol (LDL-C). CONCLUSION: This study revealed the role of the U2AF2-C1qbp-copper death regulatory axis in the development of AS, providing new targets and a theoretical basis for the treatment of AS. Targeted inhibition of U2AF2 may become an effective strategy to delay progression of AS.