Downregulation of ATP8B2 in atherosclerosis exacerbates foam cell-like pathological changes via impairing lysosomal membrane fusion.

BACKGROUND

Atherosclerosis, a major cause of global mortality, involves the transformation of macrophages into foam cells, which is a key pathological process. This study aims to elucidate the molecular mechanisms that contribute to foam cell formation and the progression of atherosclerosis.

METHODS AND RESULTS

We performed a comprehensive bioinformatics analysis of transcriptome data to identify differentially expressed genes (DEGs) associated with atherosclerosis. Using the human acute monocytic leukemia cell line THP-1, we established in vitro models of macrophages and foam cells to simulate the atherosclerotic microenvironment. Functional studies were conducted using siRNA-mediated knockdown, real-time PCR, Western blotting, and immunofluorescence imaging. Our results showed that ATP8B2 was significantly down-regulated in atherosclerotic foam cells. The downregulation of ATP8B2 led to impaired lysosomal membrane fusion, evidenced by an increase in CD63-positive compartments without a change in CD63 protein levels. Additionally, under starvation conditions, there was a significant accumulation of autophagosomes, indicating a defect in the autophagy-lysosomal pathway.

CONCLUSIONS

This study, for the first time, demonstrates that the downregulation of ATP8B2 exacerbates atherosclerosis by disrupting lysosomal membrane fusion, leading to lipid accumulation and foam cell formation. These findings provide novel insights into the pathogenesis of atherosclerosis and suggest that ATP8B2 could be a potential therapeutic target for the prevention or treatment of this disease.