Abstract
Circulating endothelial progenitor cells (EPCs) play a key role in maintaining endothelial function. Dysfunction of EPCs is associated with the cardiovascular complication of diabetes. The purpose of this study is to investigate the direct effects of hyperinsulinemia on EPCs and the underlying mechanisms. EPCs isolated from healthy adults were cultured with various concentrations of insulin (control group, without insulin; physiological insulin group, 10nM insulin and hyperinsulinemia group, 100nM insulin) with or without phosphatidylinositol-3-kinase (PI3-K) inhibitor (LY294002, 5µM), endothelial nitric oxide synthase (eNOS) inhibitor (L-NG-nitro-arginine methyl ester (L-NAME), 100µM), sodium nitroprusside (SNP, 25µM), p38 mitogen-activated protein kinase(MAPK) inhibitor (SB203580, 5µM) or extracellular signal-regulated kinases (ERK) 1/2 inhibitor (PD98059, 10µM). Proliferation, tube formation, and apoptosis of EPCs were determined. Expressions of eNOS, PI3-K, protein kinase B (Akt), p38 MAPK, and ERK 1/2 were assessed. Hyperinsulinemia caused a significant decrease in proliferation and tube formation abilities than control group. Hyperinsulinemia increased apoptosis rate of EPCs than control group. Furthermore, hyperinsulinemia downregulated phosphorylation of eNOS, PI3-K and Akt, and upregulated phosphorylation of p38 MAPK and ERK. SNP could restore impaired tube formation induced by hyperinsulinemia. P38 MAPK inhibitor but not ERK inhibitor could decrease apoptosis induced by hyperinsulinemia. Hyperinsulinemia impaired EPCs' tube formation ability by downregulation of PI-3K/Akt/eNOS pathway. Hyperinsulinemia induced apoptosis of EPCs via upregulation of p38 MAPK.
Published Version
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