UGP2, a novel target gene of TP53, inhibits endothelial cells apoptosis and atherosclerosis

The dysfunction of the endothelial lining in lesion-prone areas of the arterial vasculature significantly contributes to the pathobiology of atherosclerotic cardiovascular disease. Recent studies suggested that UDP-glucose pyrophosphorylase 2 (UGP2) plays a role in cell proliferation and survival. This study investigates the anti-apoptotic and anti-atherogenic effects of UGP2 both in vitro and in vivo. We explored the effects and mechanisms of UGP2 on apoptosis in endothelial cells using flow cytometry and Western blot analysis. Additionally, we evaluate apoptosis levels in atherosclerotic lesions with ldlr^-/- ugp2^+/- mice. Microarray analysis revealed reduced UGP2 expression in human atherosclerotic plaques. In vitro experiments demonstrated that TP53 interacts with the promoter region of the UGP2 gene, upregulating UGP2 expression. Enhanced UGP2 expression led to decreased reactive oxygen species (ROS) levels, reduced Cleaved caspase-3 expression, and lower apoptosis levels in endothelial cells. The anti-apoptotic effects of UGP2 were significantly diminished by H₂O₂. In vivo, UGP2 deficiency in ldlr^-/- mice fed a Western high-fat diet promoted atherosclerosis, increased ROS levels, and elevated Cleaved caspase-3 expression and apoptosis in atherosclerotic lesions. Our findings identify UGP2 as a novel TP53 target gene that contributes to anti-apoptotic effects by regulating ROS homeostasis via a non-canonical pathway. UGP2 represents a potential therapeutic target for ameliorating atherosclerosis-related diseases.