Quantitative proteomics identifies clusterin as a novel biomarker for atherosclerosis

Abstract

Background: Atherosclerosis (AS), the leading cause of cardiovascular disease, involves complex molecular mechanisms that remain incompletely understood, particularly in the context of diet-induced vascular lesions.

Methods: We established an AS model in Bama miniature pigs using a high-cholesterol, high-fat diet (HCFD) and performed quantitative proteomic analysis on coronary artery tissues. Key proteins were identified using protein–protein interaction (PPI) network analysis and subsequently validated by histopathological evaluation in porcine and murine coronary arteries. The underlying molecular mechanisms were elucidated using Western blot analysis.

Results: The HCFD successfully induced an atherosclerotic phenotype characterized by significantly elevated serum lipid levels. Proteomic analysis identified 108 differentially expressed proteins (DEPs) between the AS and control groups. From four identified hub proteins, we focused on clusterin (CLU), which was markedly upregulated in atherosclerotic coronary tissues, particularly within endothelial cells (ECs) and smooth muscle cells (SMCs). Mechanistically, CLU upregulation activated the LRP1/AKT signaling pathway, thereby promoting atherogenesis.

Conclusion: Our study reveals that elevated CLU expression accelerates the process of AS by activating the LRP1/AKT pathway. These data elucidate a novel pro-atherogenic role for CLU and establish the CLU/LRP1/AKT axis as a promising therapeutic target for managing AS, particularly in pathologies driven by high-fat diets.

Keywords

AKT / atherosclerosis / clusterin / LRP1 / proteomics

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