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MicroRNA-216a induces endothelial senescence and inflammation via Smad3/I?B? pathway.

ABSTRACT: Vascular endothelial senescence contributes to atherosclerosis and coronary artery disease (CAD), but the mechanisms are yet to be clarified. We identified that microRNA-216a (miR-216a) significantly increased in senescent endothelial cells. The replicative senescence model of human umbilical vein endothelial cells (HUVECs) was established to explore the role of miR-216a in endothelial ageing and dysfunction. Luciferase assay indicated that Smad3 was a direct target of miR-216a. Stable expression of miR-216a induced a premature senescence-like phenotype in HUVECs with an impairment in proliferation and migration and led to an increased adhesion to monocytes by inhibiting Smad3 expression and thereafter modulating the degradation of NF-?B inhibitor alpha (I?B?) and activation of adhesion molecules. Conversely, inhibition of endogenous miR-216a in senescent HUVECs rescued Smad3 and I?B? expression and inhibited monocytes attachment. Plasma miR-216a was significantly higher in old CAD patients (>50 years) and associated with increased 31% risk for CAD (odds ratio 1.31, 95% confidence interval 1.03-1.66; P = .03) compared with the matched healthy controls (>50 years). Taken together, our data suggested that miR-216a promotes endothelial senescence and inflammation as an endogenous inhibitor of Smad3/I?B? pathway, which might serve as a novel target for ageing-related atherosclerotic diseases.

SUBMITTER: Yang S

PROVIDER: S-EPMC5908109 | biostudies-literature | 2018 May

REPOSITORIES: biostudies-literature

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MicroRNA-216a induces endothelial senescence and inflammation via Smad3/IκBα pathway.

Yang Shujun S Mi Xuenan X Chen Yu Y Feng Congrui C Hou Zhihui Z Hui Rutai R Zhang Weili W

Journal of cellular and molecular medicine 20180307 5

Vascular endothelial senescence contributes to atherosclerosis and coronary artery disease (CAD), but the mechanisms are yet to be clarified. We identified that microRNA-216a (miR-216a) significantly increased in senescent endothelial cells. The replicative senescence model of human umbilical vein endothelial cells (HUVECs) was established to explore the role of miR-216a in endothelial ageing and dysfunction. Luciferase assay indicated that Smad3 was a direct target of miR-216a. Stable expressio ...[more]

PMID: 29512862

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Project description:Targeting microRNAs (miRs) using small chemical molecules has become a promising strategy for disease treatment. miR‑216a has been reported to be a potential therapeutic target in endothelial senescence and atherosclerosis via the Smad3/NF‑κB signaling pathway. Ginsenoside Rb2 (Rb2) is the main bioactive component extracted from the plant Panax ginseng, and is a widely used traditional Chinese medicine. In the present study, Rb2 was identified to have a high score for miR‑216a via bioinformatics analysis based on its sequence and structural features. The microscale thermophoresis experiment further demonstrated that Rb2 had a specific binding affinity for miR‑216a and the dissociation constant was 17.6 µM. In both young and senescent human umbilical vein endothelial cells (HUVECs), as well as human aortic endothelial cells, Rb2 decreased the expression of endogenous miR‑216a. Next, a replicative endothelial senescence model of HUVECs was established by infection with pre‑miR‑216a recombinant lentiviruses (Lv‑miR‑216a) and the number of population‑doubling level (PDL) was calculated. Stable overexpression of miR‑216a induced a premature senescent‑like phenotype, whereas the senescent features and increased activity of senescence‑associated β‑galactosidase (SA‑β‑gal) were reversed after Rb2 treatment. The percentage of SA‑β‑gal‑positive cells in senescent PDL25 cells transfected with Lv‑miR‑216a was decreased 76% by Rb2 treatment compared with the Lv‑miR‑216a group without Rb2 treatment (P=0.01). Mechanistically, miR‑216a inhibited Smad3 protein expression, promoted IκBα degradation and activated NF‑κB‑responsive genes, such as vascular cell adhesion molecule 1 (VCAM1), which promoted the adhesiveness of endothelial cells to monocytes. These pro‑inflammatory effects of miR‑216a were significantly suppressed by Rb2 treatment. When Smad3 was suppressed by small interfering RNA, the elevated expression levels of intercellular adhesion molecule 1 and VCAM1 induced by miR‑216a were significantly reversed. Collectively, to the best of our knowledge, the present study demonstrated for the first time that Rb2 exerted an anti‑inflammation effect on the process of endothelial cell senescence and could be a potential therapeutic drug by targeting miR‑216a.

Project description:Background: The endothelium is the first line of defence against harmful microenvironment risks, and microRNAs (miRNAs) involved in vascular inflammation may be promising therapeutic targets to modulate atherosclerosis progression. In this study, we aimed to investigate the mechanism by which microRNA-216a (miR-216a) modulated inflammation activation of endothelial cells. Methods. A replicative senescence model of human umbilical vein endothelial cells (HUVECs) was established, and population-doubling levels (PDLs) were defined during passages. PDL8 HUVECs were transfected with miR-216a mimics/inhibitor or small interfering RNA (siRNA) of SMAD family member 7 (Smad7). Real-time PCR and Western blot assays were performed to detect the regulatory role of miR-216a on Smad7 and NF-?B inhibitor alpha (I?B?) expression. The effect of miR-216a on adhesive capability of HUVECs to THP-1 cells was examined. MiR-216a and Smad7 expression in vivo were measured using human carotid atherosclerotic plaques of the patients who underwent carotid endarterectomy (n = 41).Results: Luciferase assays showed that Smad7 was a direct target of miR-216a. Smad7 mRNA expression, negatively correlated with miR-216a during endothelial aging, was downregulated in senescent PDL44 cells, compared with young PDL8 HUVECs. MiR-216a markedly increased endothelial inflammation and adhesive capability to monocytes in PDL8 cells by promoting the phosphorylation and degradation of I?B? and then activating NF-?B signalling pathway. The effect of miR-216a on endothelial cells was consistent with that blocked Smad7 by siRNAs. When inhibiting endogenous miR-216a, the Smad7/I?B? expression was rescued, which led to decreased endothelial inflammation and monocytes recruitment. In human carotid atherosclerotic plaques, Smad7 level was remarkably decreased in high miR-216a group compared with low miR-216a group. Moreover, miR-216a was negatively correlated with Smad7 and I?B? levels and positively correlated with interleukin 1 beta (IL1?) expression in vivo.Conclusion: In summary, our findings suggest a new mechanism of vascular endothelial inflammation involving Smad7/I?B? signalling pathway in atherosclerosis.

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MicroRNA-216a induces endothelial senescence and inflammation via Smad3/I?B? pathway.

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MicroRNA-216a induces endothelial senescence and inflammation via Smad3/IκBα pathway.

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