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.
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Authors | Cheng Huang, Guang Li, Haojian Dong, Shuo Sun, Haimin Chen, Demou Luo, Ling Sun, Xida Li, Zhujun Chen, Huijian Yang, Shuisheng Wei, Yingling Zhou |
Journal | International journal of molecular medicine
(Int J Mol Med)
Vol. 36
Issue 1
Pg. 239-48
(Jul 2015)
ISSN: 1791-244X [Electronic] Greece |
PMID | 25902041
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
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Chemical References |
- Aminopyridines
- Insulin Receptor Substrate Proteins
- MIRN155 microRNA, human
- MicroRNAs
- Morpholines
- NVP-BKM120
- Phosphoinositide-3 Kinase Inhibitors
- Nitric Oxide
- Nitric Oxide Synthase Type III
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Topics |
- Adult
- Aged
- Aminopyridines
(pharmacology)
- Cells, Cultured
- Diabetes Mellitus
(genetics)
- Enzyme Activation
(genetics)
- Female
- Human Umbilical Vein Endothelial Cells
(metabolism)
- Humans
- Insulin Receptor Substrate Proteins
(biosynthesis, genetics)
- Insulin Resistance
(genetics)
- Male
- MicroRNAs
(biosynthesis, genetics)
- Middle Aged
- Morpholines
(pharmacology)
- Nitric Oxide
(biosynthesis)
- Nitric Oxide Synthase Type III
(biosynthesis)
- Phosphoinositide-3 Kinase Inhibitors
- Phosphorylation
- Transfection
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