title: Arg⁹⁷² insulin receptor substrate-1 inhibits endothelial nitric oxide synthase expression in human endothelial cells by upregulating microRNA-155.
abstract: The dysregulation of nitric oxide (NO) synthesis attributable to the abnormal expression/activity of endothelial NO synthase (eNOS) is considered to be a major characteristic of insulin-resistant states, as well as an essential contributor to the pathogenesis of cardiovascular diseases. The Arg972 insulin receptor substrate-1 (IRS-1) is associated with insulin resistance. In the present study, we investigated the association between Arg972 IRS-1 and eNOS expression/activity in human subjects and in primary cultures of human endothelial cells. Data from 832 human subjects revealed that heterozygous and homozygous Arg972 IRS-1 carriers had significantly lower levels of plasma eNOS and nitrite/nitrate than the homozygous wild-type (WT) IRS-1 carriers. Human umbilical vein endothelial cells (HUVECs) established from delivering mothers expressing heterozygous Arg972 IRS-1 had significantly lower eNOS expression/activity and higher miR-155 levels than those expressing WT homozygous IRS-1. The overexpression of IRS-1 and Arg972 IRS-1 in the HUVECs, respectively, decreased and increased the miR-155 expression level. In addition, the overexpression of IRS-1 in the HUVECs significantly increased eNOS expression; this effect was reversed by transfection with mature miR-155 mimic or treatment with the selective phosphatidylinositol-3 kinase (PI3K) inhibitor, BKM120. On the other hand, the overexpression of Arg972 IRS-1 markedly decreased eNOS expression and this effect was reversed by transfection with antagomir-155. On the whole, our in vivo data demonstrate that Arg972 IRS-1 is associated with decreased plasma eNOS and nitrite/nitrate levels in human subjects. Our in vitro data demonstrate that Arg972 IRS-1 inhibits eNOS expression in human endothelial cells by upregulating miR-155 expression through the impairment of PI3K signaling. The present study provides new insight into the pathophysiological role of Arg972 IRS-1 in cardiovascular diseases.
authors.affiliation: Department of Intensive Care Medicine, Guangdong General Hospital, Guangzhou, Guangdong 510080, P.R. China.
authors.forename: Cheng
authors.initials: C
authors.lastname: Huang
authors.affiliation: Department of Intensive Care Medicine, Guangdong General Hospital, Guangzhou, Guangdong 510080, P.R. China.
authors.forename: Guang
authors.initials: G
authors.lastname: Li
authors.affiliation: Department of Intensive Care Medicine, Guangdong General Hospital, Guangzhou, Guangdong 510080, P.R. China.
authors.forename: Haojian
authors.initials: H
authors.lastname: Dong
authors.affiliation: Department of Intensive Care Medicine, Guangdong General Hospital, Guangzhou, Guangdong 510080, P.R. China.
authors.forename: Shuo
authors.initials: S
authors.lastname: Sun
authors.affiliation: Department of Intensive Care Medicine, Guangdong General Hospital, Guangzhou, Guangdong 510080, P.R. China.
authors.forename: Haimin
authors.initials: H
authors.lastname: Chen
authors.affiliation: Department of Intensive Care Medicine, Guangdong General Hospital, Guangzhou, Guangdong 510080, P.R. China.
authors.forename: Demou
authors.initials: D
authors.lastname: Luo
authors.affiliation: Department of Intensive Care Medicine, Guangdong General Hospital, Guangzhou, Guangdong 510080, P.R. China.
authors.forename: Ling
authors.initials: L
authors.lastname: Sun
authors.affiliation: Department of Intensive Care Medicine, Guangdong General Hospital, Guangzhou, Guangdong 510080, P.R. China.
authors.forename: Xida
authors.initials: X
authors.lastname: Li
authors.affiliation: Department of Intensive Care Medicine, Guangdong General Hospital, Guangzhou, Guangdong 510080, P.R. China.
authors.forename: Zhujun
authors.initials: Z
authors.lastname: Chen
authors.affiliation: Department of Intensive Care Medicine, Guangdong General Hospital, Guangzhou, Guangdong 510080, P.R. China.
authors.forename: Huijian
authors.initials: H
authors.lastname: Yang
authors.affiliation: Department of Intensive Care Medicine, Guangdong General Hospital, Guangzhou, Guangdong 510080, P.R. China.
authors.forename: Shuisheng
authors.initials: S
authors.lastname: Wei
authors.affiliation: Department of Intensive Care Medicine, Guangdong General Hospital, Guangzhou, Guangdong 510080, P.R. China.
authors.forename: Yingling
authors.initials: Y
authors.lastname: Zhou
mesh_terms: D000328:Adult; D000368:Aged; D000631:Aminopyridines / Q000494:pharmacology; D002478:Cells, Cultured; D003920:Diabetes Mellitus / Q000235:genetics; D004789:Enzyme Activation / Q000235:genetics; D005260:Female; D061307:Human Umbilical Vein Endothelial Cells / Q000378:metabolism; D006801:Humans; D055504:Insulin Receptor Substrate Proteins / Q000096:biosynthesis / Q000235:genetics*; D007333:Insulin Resistance / Q000235:genetics; D008297:Male; D035683:MicroRNAs / Q000096:biosynthesis / Q000235:genetics*; D008875:Middle Aged; D009025:Morpholines / Q000494:pharmacology; D009569:Nitric Oxide / Q000096:biosynthesis*; D052250:Nitric Oxide Synthase Type III / Q000096:biosynthesis*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010766:Phosphorylation; D014162:Transfection
chemical_list: D000631:Aminopyridines; D055504:Insulin Receptor Substrate Proteins; C524942:MIRN155 microRNA, human; D035683:MicroRNAs; D009025:Morpholines; C571178:NVP-BKM120; D000081082:Phosphoinositide-3 Kinase Inhibitors; D009569:Nitric Oxide; D052250:Nitric Oxide Synthase Type III