Hyperglycemia is a major factor in vascular endothelial injury that finally leads to a cardiovascular event.Steroid receptor coactivators (SRCs) are a group of non-DNA binding proteins that induce structural changes in steroid receptors (nuclear receptors) critical for transcriptional activation.SRCs,namely,SRC-1,SRC-2,and SRC-3,are implicated in the regulation of vascular homeostasis.In this study we investigate the role of SRCs in hyperglycemia-induced endothelial injury.Aortic endothelial cells were prepared from normal and diabetic rats,respectively.Diabetic rats were prepared by injection of streptozotocin (50 mg/kg,i.p.).The expression levels of SRC-1 and SRC-3 were significantly decreased in endothelial cells from the diabetic rats.Similar phenomenon was also observed in aortic endothelial cells from the normal rats treated with a high glucose (2.5 mM) for 4 h or 8 h.The expression levels of SRC-2 were little affected by hyperglycemia.Overexpression of SRC-1 and SRC-3 in high glucose-treated endothelial cells significantly increased the cell viability,suspended cell senescence,and inhibited cell apoptosis compared with the control cells.We further showed that overexpression of SRC-1 and SRC-3 markedly suppressed endothelial injury through restoring nitric oxide production,upregulating the expression of antioxidant enzymes (SOD,GPX,and CAT),and activating the PI3K/Akt pathway.The beneficial effects of SRC-1 and SRC-3 overexpression were blocked by treatment with the PI3K inhibitor LY294002 (10 mM) or with the Akt inhibitor MK-2206 (100 nM).In conclusion,hyperglycemia decreased SRC-1 and SRC-3 expression levels in rat aortic endothelial cells.SRC-1 and SRC-3 overexpression might protect against endothelial injury via inhibition of oxidative stress and activation of PI3K/Akt pathway.