title: Essential role of microRNA-155 in regulating endothelium-dependent vasorelaxation by targeting endothelial nitric oxide synthase.
abstract: Nitric oxide generated by endothelial nitric oxide synthase (eNOS) plays an important role in maintaining cardiovascular homeostasis. Under various pathological conditions, abnormal expression of eNOS contributes to endothelial dysfunction and the development of cardiovascular diseases. A variety of pathological stimuli has been reported to decrease eNOS expression mainly through decreasing eNOS mRNA stability by regulating the binding of several cytosolic proteins to the cis-acting sequences within eNOS mRNA 3' untranslated regions. However, the detailed mechanisms remain elusive. Because microRNAs inhibit gene expression through binding to the 3' untranslated regions of their target mRNAs, microRNAs may be the important posttranscriptional modulators of eNOS expression. Here, we provided evidence that eNOS is a direct target of miR-155. Overexpression of miR-155 decreased, whereas inhibition of miR-155 increased, eNOS expression and NO production in human umbilical vein endothelial cells and acetylcholine-induced endothelium-dependent vasorelaxation in human internal mammary arteries. Inflammatory cytokines including tumor necrosis factor-α increased miR-155 expression. Inhibition of miR-155 reversed tumor necrosis factor-α-induced downregulation of eNOS expression and impairment of endothelium-dependent vasorelaxation. Moreover, we observed that simvastatin attenuated tumor necrosis factor-α-induced upregulation of miR-155 and ameliorated the effects of tumor necrosis factor-α on eNOS expression and endothelium-dependent vasodilation. Simvastatin decreased miR-155 expression through interfering mevalonate-geranylgeranyl-pyrophosphate-RhoA signaling pathway. These findings indicated that miR-155 is an essential regulator of eNOS expression and endothelium-dependent vasorelaxation. Inhibition of miR-155 may be a new therapeutic approach to improve endothelial dysfunction during the development of cardiovascular diseases.
authors.affiliation: Reproductive Medicine Center, Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing, China.
authors.forename: Hai-Xiang
authors.initials: HX
authors.lastname: Sun
authors.forename: De-Yi
authors.initials: DY
authors.lastname: Zeng
authors.forename: Ruo-Tian
authors.initials: RT
authors.lastname: Li
authors.forename: Rui-Ping
authors.initials: RP
authors.lastname: Pang
authors.forename: Hui
authors.initials: H
authors.lastname: Yang
authors.forename: Ya-Li
authors.initials: YL
authors.lastname: Hu
authors.forename: Qun
authors.initials: Q
authors.lastname: Zhang
authors.forename: Yue
authors.initials: Y
authors.lastname: Jiang
authors.forename: Lin-Yan
authors.initials: LY
authors.lastname: Huang
authors.forename: Yong-Bo
authors.initials: YB
authors.lastname: Tang
authors.forename: Gui-Jun
authors.initials: GJ
authors.lastname: Yan
authors.forename: Jia-Guo
authors.initials: JG
authors.lastname: Zhou
mesh_terms: D002478:Cells, Cultured; D015536:Down-Regulation / Q000187:drug effects / Q000235:genetics; D004730:Endothelium, Vascular / Q000187:drug effects / Q000378:metabolism*; D061307:Human Umbilical Vein Endothelial Cells / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology; D008323:Mammary Arteries / Q000187:drug effects / Q000378:metabolism*; D035683:MicroRNAs / Q000235:genetics* / Q000378:metabolism; D052250:Nitric Oxide Synthase Type III / Q000235:genetics / Q000378:metabolism*; D019821:Simvastatin / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D014664:Vasodilation / Q000187:drug effects / Q000235:genetics*
chemical_list: D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; C524942:MIRN155 microRNA, human; D035683:MicroRNAs; D014409:Tumor Necrosis Factor-alpha; D019821:Simvastatin; D052250:Nitric Oxide Synthase Type III