Macrophage CBX4 Potentiates Atherosclerosis by its SUMO E3 Ligase Activity

Atherosclerosis (AS) is the leading cause of cardiovascular disease and mortality worldwide. Despite extensive research, there remains an urgent need for novel therapeutic strategies. By integrating genomic data from the Gene Expression Omnibus (GEO) with human atherosclerotic tissues, we identified enrichment of sumoylation pathways in AS, with chromobox 4 (CBX4), a SUMO E3 ligase, being significantly upregulated. This study aims to investigate the role of CBX4 in macrophages during atherosclerosis progression and its potential molecular mechanisms.

We analyzed gene expression profiles from human atherosclerotic segments to identify differentially expressed pathways. High-fat diet (HFD)-challenged apolipoprotein E-deficient (ApoE^-/-) mice were used to examine CBX4 expression in macrophages. The impact of CBX4 on atherosclerosis was assessed using macrophage-specific CBX4 knockdown and overexpression models. Mechanistically, we evaluated the interaction between CBX4 and hypoxia-inducible factor 1-alpha (HIF-1α) and its effect on sumoylation and transcriptional activity.

CBX4 expression was elevated in macrophages from atherosclerotic lesions of HFD-fed ApoE^-/- mice. Macrophage-specific CBX4 knockdown significantly alleviated HFD-induced AS, whereas CBX4 overexpression exacerbated atherosclerotic progression. Mechanistically, CBX4 directly interacted with HIF-1α and promoted its sumoylation, leading to increased HIF-1α transcriptional activity, which may contribute to AS development.

Our findings highlight CBX4-promoted SUMOylation of HIF-1α exacerbates AS progression. Targeting CBX4 may represent a promising therapeutic strategy for mitigating atherosclerosis progression.