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

Abstract Dysfunction of the endothelial lining of lesion-prone areas of the arterial vasculature is an important contributor to the pathobiology of atherosclerotic cardiovascular disease. Recent studies have indicated that UDP-glucose pyrophosphorylase 2(UGP2) is implicated in cell proliferation and survival. Here we investigated the anti-apoptosis and anti-atherogenic effect of UGP2 in vitro and in vivo.Here, we explored the effects and mechanisms of UGP2 on apoptosis in endothelial cells by flow cytometer and Western blot analyses. And we engineered ldlr −/− ugp2 +/− double-deficient mice to evaluated the apoptosis levels in atherosclerotic lesion. A microarray analysis showed that the expression of UGP2 was reduced in human atherosclerotic plaques. In vitro experiments revealed that TP53 interacted with the promotor region of the UGP2 gene, which upregulated UGP2 expression. Augmentation of UGP2 expression downregulated ROS levels, the expressions of Cleaved caspase-3 and apoptosis levels in endothelial cells, and this inhibitory effects of UGP2 on cell apoptosis could be significantly abolished by H 2 O 2 . In vivo experiments using ldlr −/− ugp2 +/− mice fed a Western high-fat diet demonstrated that UGP2 deficiency promoted atherosclerosis, and increased the levels of ROS, expressions of Cleaved caspase-3 and apoptosis cells in atherosclerotic lesions. Thus, our results provide evidence for UGP2 as a novel target gene of TP53 contributes to anti-apoptosis effect linking to ROS homeostasis differ from canonical pathway, and we suggested that UGP2 could act as potential therapeutic targets to ameliorate atherosclerosis-related diseases.