MicroRNA 217 Modulates Endothelial Cell Senescence via Silent Information Regulator 1

Menghini, Rossella; Casagrande, Viviana; Cardellini, Marina; Martelli, Eugenio; Terrinoni, Alessandro; Amati, Francesca; Vasa‐Nicotera, Mariuca; Ippoliti, Arnaldo; Novelli, Giuseppe; Melino, Gerry; Lauro, Renato; Federici, Massimo

doi:10.1161/circulationaha.109.864629

Cited by 434 publications

(365 citation statements)

References 34 publications

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“…Moreover, our study also showed that miR-181a decreases SIRT1 protein levels in mouse liver. Previous studies have shown that SIRT1 can be regulated by multiple miRNAs, such as miR-9, miR-22, miR-34a, miR-132, miR-199a and miR-217 in some different biological processes [27,[30][31][32]. In our experiment, we similarly observed the inhibitory effect of these miRNAs.…”

Section: Discussionsupporting

confidence: 82%

Downregulation of miR-181a upregulates sirtuin-1 (SIRT1) and improves hepatic insulin sensitivity

et al. 2012

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Aims/hypothesis Sirtuin-1 (SIRT1) is a potential therapeutic target to combat insulin resistance and type 2 diabetes. This study aims to identify a microRNA (miRNA) targeting SIRT1 to regulate hepatic insulin sensitivity. Methods Luciferase assay combined with mutation and immunoblotting was used to screen and verify the bioinformatically predicted miRNAs. miRNA and mRNA levels were measured by real-time PCR. Insulin signalling was detected by immunoblotting and glycogen synthesis. Involvement of SIRT1 was studied with adenovirus, inhibitor and SIRT1-deficient hepatocytes. The role of miR-181a in vivo was explored with adenovirus and locked nucleic acid antisense oligonucleotides. Results miR-181a targets the 3′ untranslated region (3′UTR) of Sirt1 mRNA through a miR-181a binding site, and downregulates SIRT1 protein abundance at the translational level. miR-181a is increased in insulin-resistant cultured hepatocytes and liver, and in the serum of diabetic patients. Overexpression of miR-181a decreases SIRT1 protein levels and activity, and causes insulin resistance in hepatic cells. Inhibition of miR-181a by antisense oligonucleotides increases SIRT1 protein levels and activity, and improves insulin sensitivity in hepatocytes. Ectopic expression of SIRT1 abrogates the effect of miR-181a on insulin sensitivity, and inhibition of SIRT1 activity or SIRT1 deficiency markedly attenuated the improvement in insulin sensitivity induced by antisense miR-181a. In addition, overexpression of miR181a by adenovirus impairs hepatic insulin signalling, and intraperitoneal injection of locked nucleic acid antisense oligonucleotides for miR-181a improves glucose homeostasis in diet-induced obesity mice. Conclusions/interpretation miR-181a regulates SIRT1 and improves hepatic insulin sensitivity. Inhibition of miR-181a might be a potential new strategy for treating insulin resistance and type 2 diabetes.

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Section: Discussionsupporting

confidence: 82%

Downregulation of miR-181a upregulates sirtuin-1 (SIRT1) and improves hepatic insulin sensitivity

et al. 2012

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“…It is estimated that approximately one‐third of all animal genes are controlled by microRNAs, and thus, microRNAs exhibit a wide range of biological processes including aging (Breving & Esquela‐Kerscher, 2010). Indeed, several earlier studies were directed to examine the relationship between microRNAs and endothelial cell senescence (Menghini et al ., 2009; Zhao et al ., 2010; Jong et al ., 2013; Olivieri et al ., 2013; Zhu et al ., 2013). Our present comprehensive microarray analysis revealed that the microRNA with the third highest augmented expression in senescent HUVECs was miR‐22‐3p and that it had a binding site on the 3′ UTR of VASH1 mRNA.…”

Section: Discussionmentioning

confidence: 99%

Age‐associated downregulation of vasohibin‐1 in vascular endothelial cells

2016

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SummaryVasohibin‐1 (VASH1) is an angiogenesis‐inhibiting factor synthesized by endothelial cells (ECs) and it also functions to increase stress tolerance of ECs, which function is critical for the maintenance of vascular integrity. Here, we examined whether the expression of VASH1 would be affected by aging. We passaged human umbilical vein endothelial cells (HUVECs) and observed that VASH1 was downregulated in old HUVECs. This decrease in VASH1 expression with aging was confirmed in mice. To explore the mechanism of this downregulation, we compared the expression of microRNAs between old and young HUVECs by performing microarray analysis. Among the top 20 microRNAs that were expressed at a higher level in old HUVECs, the third highest microRNA, namely miR‐22‐3p, had its binding site on the 3′ UTR of VASH1 mRNA. Experiments with microRNA mimic and anti‐miR revealed that miR‐22‐3p was involved at least in part in the downregulation of VASH1 in ECs during replicative senescence. We then clarified the significance of this defective expression of VASH1 in the vasculature. When a cuff was placed around the femoral arteries of wild‐type mice and VASH1‐null mice, neointimal formation was augmented in the VASH1‐null mice accompanied by an increase in adventitial angiogenesis, macrophage accumulation in the adventitia, and medial/neointimal proliferating cells. These results indicate that in replicative senescence, the downregulation of VASH1 expression in ECs was caused, at least in part, by the alteration of microRNA expression. Such downregulation of VASH1 might be involved in the acceleration of age‐associated vascular diseases.

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“…Increasing evidence suggest a significant role of miRNAs as mediators in vascular ageing and inflammatory process in animal models and human studies 4, 5. To date, several miRNAs have been identified to regulate the process of endothelial senescence and inflammation, such as miR‐217,6 miR‐34a,7 miR‐146a8, 9 and miR‐181b 10. Nevertheless, the effect of miRNAs that regulate endothelial cell ageing and inflammation has not been fully clarified.…”

Section: Introductionmentioning

confidence: 99%

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

Yang

Chen

et al. 2018

J Cellular Molecular Medi

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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‐κB inhibitor alpha (IκBα) and activation of adhesion molecules. Conversely, inhibition of endogenous miR‐216a in senescent HUVECs rescued Smad3 and IκBα 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/IκBα pathway, which might serve as a novel target for ageing‐related atherosclerotic diseases.

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MicroRNA 217 Modulates Endothelial Cell Senescence via Silent Information Regulator 1

Cited by 434 publications

References 34 publications

Downregulation of miR-181a upregulates sirtuin-1 (SIRT1) and improves hepatic insulin sensitivity

Downregulation of miR-181a upregulates sirtuin-1 (SIRT1) and improves hepatic insulin sensitivity

Age‐associated downregulation of vasohibin‐1 in vascular endothelial cells

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

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