Dopamine beta-hydroxylase mediates atherosclerosis progression by regulating copper metabolism via PHOX2A

Atherosclerosis (AS) is a major cardiovascular disease whose underlying molecular mechanisms remain incompletely understood. This study investigates the role of dopamine beta-hydroxylase (DBH) in AS pathogenesis and its regulation of copper metabolism via the transcription factor PHOX2A. Through transcriptomic profiling of aortic tissues from ApoE⁻/⁻ mice fed a high-fat diet, we identified 2891 differentially expressed genes (DEGs) between AS and control mice, with DBH being significantly upregulated. DBH expression was also elevated in the serum of AS patients and in ox-LDL-treated human vascular smooth muscle cells (HVSMCs). Mechanistically, we demonstrate that PHOX2A directly activates the DBH promoter, and that DBH knockdown attenuates ox‑LDL‑induced apoptosis and lipid accumulation in HVSMCs while PHOX2A overexpression exacerbates these effects. Importantly, DBH knockdown in ApoE⁻/⁻ mice not only reduced atherosclerotic plaque burden and improved serum lipid profiles but also restored serum copper concentrations and altered the expression of cuproptosis‑related proteins (FDX1, LIAS, DLAT). These findings identify DBH as a key mediator of AS progression linked to PHOX2A‑dependent regulation of copper metabolism and cuproptosis, suggesting that targeting the DBH/PHOX2A axis may represent a novel therapeutic strategy for AS.