Essential Role of MicroRNA-155 in Regulating Endothelium-Dependent Vasorelaxation by Targeting Endothelial Nitric Oxide Synthase

Abstract

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 acetylcholineinduced 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.

Inhibition of MicroRNA‐155 Supports Endothelial Tight Junction Integrity Following Oxygen‐Glucose Deprivation

“…No significant differences in cell viability were detected between OGD/I, OGD/IC, OGD/M, and OGD/MC samples. Another possible regulator of the endothelial integrity, endothelial NO synthase, is directly targeted by miR‐155 16, 18. NO is involved in protection of the BBB from hypoxia/reoxygenation‐mediated injury 22.…”

“…miR‐155 expression is limited to hematopoietic cells and cells involved in vascular remodeling, including endothelial cells 15, 16. Our previous studies demonstrated that miR‐155 negatively regulates proangiogenic signaling pathways in mouse brain endothelial cells: inhibition of miR‐155 significantly enhanced while overexpression significantly inhibited the in vitro endothelial morphogenesis 17.…”

Statins as Regulators of Redox State in the Vascular Endothelium: Beyond Lipid Lowering

“…Importantly, this effect was attenuated by simvastatin, but the beneficial actions of the statin were abolished by co-incubation with mevalonate or GGPP. Interestingly, they were mimicked by inhibition of RhoA, suggesting that the mevalonate/ GGPP/RhoA pathway underlies the observed effects of simvastatin on miR-155 expression (103). The increased expression of eNOS mediated by statins translates into improved endothelial function, as evidenced in animal models of age-related (27) and high-fat-diet-induced (119) endothelial dysfunction.…”

Effect of endothelial microRNAs on blood pressure homeostasis

“…Previous studies have demonstrated that endothelial miRNAs control endothelial functions and are implicated in the onset and development of cardiovascular disease 9,[19][20][21][22] . However, the role of endothelial miRNAs in BP homeostasis has been poorly understood.…”