Overexpression of steroid receptor coactivators alleviates hyperglycemia-induced endothelial cell injury in rats through activating the PI3K/Akt pathway


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 (25 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.

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Financial support was provided by the Key Program for Social Development, Science and Technology of Shaanxi Province, China (2016SF-077), and the Social Development Guidance Program-Medical Research Project of Xi’an, China (SF1509).

Author contributions

XJQ and CLL designed research and wrote the paper; XJQ, CLL, MZS, LZ, and XLL performed research; and XJQ, CLL, LZ, and XLL analyzed data.

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Correspondence to Xiao-juan Quan.

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Quan, X., Liang, C., Sun, M. et al. Overexpression of steroid receptor coactivators alleviates hyperglycemia-induced endothelial cell injury in rats through activating the PI3K/Akt pathway. Acta Pharmacol Sin 40, 648–657 (2019). https://doi.org/10.1038/s41401-018-0109-4

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  • diabetics
  • streptozotocin
  • hyperglycemia
  • endothelial cells
  • steroid receptor coactivators
  • cell senescence
  • cell apoptosis
  • oxidative stress
  • PI3K/Akt pathway
  • LY294002
  • MK-2206