DBH is upregulated in atherosclerosis and, under activation by the transcription factor PHOX2A, promotes ox-LDL-induced apoptosis and lipid accumulation in vascular smooth muscle cells; DBH knockdown in ApoE-/- mice reduced plaque burden, improved lipids, restored serum copper, and altered cuproptosis-related proteins, suggesting the DBH/PHOX2A axis as a potential therapeutic target.
Transcriptomic profiling of aortas from high-fat-diet-fed ApoE-/- mice identified 2891 differentially expressed genes versus control mice, with DBH significantly upregulated.
DBH expression is elevated in the serum of atherosclerosis patients and in ox-LDL-treated human vascular smooth muscle cells (HVSMCs).
The transcription factor PHOX2A directly activates the DBH promoter.
DBH knockdown attenuates ox-LDL-induced apoptosis and lipid accumulation in HVSMCs, whereas PHOX2A overexpression exacerbates these effects.
DBH knockdown in ApoE-/- mice reduced atherosclerotic plaque burden and improved serum lipid profiles.
DBH knockdown in ApoE-/- mice restored serum copper concentrations and altered expression of cuproptosis-related proteins FDX1, LIAS, and DLAT.
The authors conclude that DBH mediates AS progression via PHOX2A-dependent regulation of copper metabolism and cuproptosis, and that targeting the DBH/PHOX2A axis may be a novel therapeutic strategy.
This study looked at why atherosclerosis, the buildup of fatty plaques in arteries, develops. By comparing artery tissue from mice prone to atherosclerosis fed a high-fat diet with control mice, the researchers found thousands of genes with altered activity. One of them, DBH, was notably more active in diseased mice. DBH levels were also higher in blood from patients with atherosclerosis and in human artery muscle cells exposed to oxidized cholesterol (ox-LDL). The researchers found that a protein called PHOX2A switches on the DBH gene. In cell experiments, reducing DBH lowered cell death and fat buildup caused by oxidized cholesterol, while boosting PHOX2A made these problems worse. In atherosclerosis-prone mice, lowering DBH reduced plaque, improved blood fats, restored blood copper levels, and changed proteins involved in cuproptosis, a copper-dependent form of cell death. This research suggests that the DBH/PHOX2A pathway and copper handling may play a role in atherosclerosis and could become a treatment target. However, the work was done mainly in mice and cultured cells, with a limited look at patient blood, so it is an early step and does not show that treatments aimed at this pathway would work in people.
Xue Q, Feng G, Hu J, Li F, Tang S. (2026). Dopamine beta-hydroxylase mediates atherosclerosis progression by regulating copper metabolism via PHOX2A.. European journal of histochemistry : EJH. https://doi.org/10.4081/ejh.2026.4586