Atherosclerosis-Associated Endothelial Cell Apoptosis by MiR-429-Mediated Down Regulation of Bcl-2

Zhang, Tao; Tian, Feng; Wang, Jing; Jing, Jing; Zhou, Shanshan; Chen, Yundai

doi:10.1159/000438511

Cited by 50 publications

(39 citation statements)

References 35 publications

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“…Among the available models, the apoE -/- mouse was the first and most widely used for this purpose. Loss of apoE gene expression in this animal compromises the hepatic clearance of VLDL and LDL, leading to spontaneous hypercholesterolemia [1, 3, 7]. Moreover, apoE -/- mice exhibit impaired vasodilation and enhanced vasoconstriction responsiveness, which are hallmarks of endothelial dysfunction in this experimental model and in atherosclerotic humans [4, 5, 7].…”

Section: Introductionmentioning

confidence: 99%

Sildenafil (Viagra®) Prevents Cox-1/ TXA2 Pathway-Mediated Vascular Hypercontractility in ApoE-/- Mice

Leal

Dias

Porto³

et al. 2017

Cell Physiol Biochem

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Background/Aims: The atherosclerotic apolipoprotein E-deficient (apoE^-/-) mouse exhibits impaired vasodilation and enhanced vasoconstriction responsiveness. The objectives of this study were: a) to determine the relative contribution of cyclooxygenases (Cox-1 and Cox-2), thromboxane A2 (TXA2) and endothelin-1 (ET-1) to enhancing vascular hyperresponsiveness in this model of atherosclerosis and b) to investigate the beneficial effects of the phosphodiesterase 5 inhibitor sildenafil on this endothelial dysfunction. Methods: Adult male apoE^-/- mice were treated with sildenafil (40 mg/kg/day, for 3 weeks) and compared with non-treated ApoE^-/- and wild-type mice. The beneficial effects of sildenafil on vascular contractile response to phenylephrine (PE) in aortic rings were evaluated before and after incubation with Cox-1 (SC-560) or Cox-2 (NS-398) inhibitors or the TP antagonist SQ-29548, and on contractile responsiveness to ET-1. Results: ApoE^-/- mice exhibited enhanced vasoconstriction to PE (R_max ∼35%, p<0.01), which was prevented by treatment with sildenafil. The enhanced PE-induced contractions were abolished by both Cox-1 inhibition and TP antagonist, but were not modified by Cox-2 inhibition. Aortic rings from ApoE^-/- mice also exhibited enhanced contractions to ET-1 (R_max ∼30%, p<0.01), which were attenuated in sildenafil-treated ApoE^-/- mice. In addition, we observed augmented levels of vascular proinflammatory cytokines in ApoE^-/- mice, which were partially corrected by treatment with sildenafil (IL-6, IL-10/IL-6 ratio and MCP-1). Conclusion: The present data show that the Cox-1/TXA2 pathway prevails over the Cox-2 isoform in the mediation of vascular hypercontractility observed in apoE^-/-mice. The results also show a beneficial effect of sildenafil on this endothelial dysfunction and on the proinflammatory cytokines in atherosclerotic animals, opening new perspectives for the treatment of other endothelium-related cardiovascular abnormalities.

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Section: Introductionmentioning

confidence: 99%

Sildenafil (Viagra®) Prevents Cox-1/ TXA2 Pathway-Mediated Vascular Hypercontractility in ApoE-/- Mice

Leal

Dias

Porto³

et al. 2017

Cell Physiol Biochem

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“…Previous studies have declared that the mechanisms underlying miRNA regulation of endothelial apoptosis are often attributed to targeting critical genes or the pivotal pathways related to apoptosis [36, 37]. Here, we discovered that miR-210 regulated endothelial apoptosis by targeting PDK1.…”

Section: Discussionmentioning

confidence: 68%

MicroRNA-210 induces endothelial cell apoptosis by directly targeting PDK1 in the setting of atherosclerosis

et al. 2017

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BackgroundAtherosclerosis is a chronically inflammatory disease and one of the leading causes of deaths worldwide. Endothelial cell apoptosis plays a crucial role in its development. Several microRNAs (miRNAs) are reportedly involved in atherosclerotic plaque formation, including miRNA-210 (miR-210). However, the underlying mechanism of its role in endothelial cell apoptosis during atherosclerosis is still largely unknown.MethodsA mouse model with atherosclerosis induced by a high-fat diet (HFD) was built in ApoE (-/-) mice. The levels of endothelial cell apoptosis were determined via flow cytometry. The expressions of miR-210 and PDK1 in purified CD31+ endothelial cells from mouse aorta were measured via RT-qPCR and western blot. Binding between miR-210 and the 3′-untranslated region (UTR) of PDK1 mRNA was predicted using bioinformatics analyses and confirmed with a dual luciferase reporter assay. The effects of miR-210 were further analyzed in an in vitro model using human aortic endothelial cells (HAECs) treated with oxidized low-density lipoprotein (ox-LDL).ResultsWe found that the HFD mice developed atherosclerosis in 12 weeks and had a significantly higher percentage of endothelial cell apoptosis. The upregulated level of miR-210 in the HFD mice and HAECs inversely correlated with the level of PDK1. Inhibiting miR-210 expression significantly reduced HAEC apoptosis, as evidenced by the results of the MTT and flow cytometry experiments. Further analysis identified PDK1 as the target of miR-210 and showed that PDK1 overexpression reversed the pro-apoptotic effect of miR-210 through mediation of the P13K/Akt/mTOR pathways.ConclusionOur study suggests a novel role for miR-210 in the progression of atherosclerosis through the regulation of endothelial apoptosis. This indicates that miR-210 might have potential in treatment of atherosclerosis.

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“…Moreover, a growing body of recent data has shown that circulating miRs could influence the development and progression of vascular diseases, including atherosclerosis [24,25]. Although atherosclerosis is common in clinical practice, the mechanisms of its genesis have …”

Section: Discussionmentioning

confidence: 99%

Plasma MicroRNA-29c Levels Are Associated with Carotid Intima-Media Thickness and is a Potential Biomarker for the Early Detection of Atherosclerosis

Huang¹,

Li²,

Huang³

et al. 2018

Cell Physiol Biochem

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Background/Aims: Atherosclerosis is a serious disease that increases the risk of myocardial infarction and ischemic stroke. Previous studies have demonstrated that microRNA (miR)-29c could play significant roles in atherosclerosis via regulating inflammatory processes. However, the relationship between miR-29c and carotid intima-media thickness (CIMT) remains unknown. This study investigated associations between miR-29c and atherosclerosis and tested whether plasma miR-29c levels could be used to detect atherosclerosis. Methods: Plasma miR-29c levels were estimated by quantitative real-time PCR, and CIMT was measured by carotid ultrasound. Associations between miR-29c and CIMT were assessed by Spearman’s correlation coefficient and multiple linear regression analyses. Results: In total, 170 participants were divided into the study (CIMT ≥0.9 mm) and control (CIMT < 0.9 mm) groups. The study group showed higher C-reactive protein (CRP) and miR-29c relative expression levels compared with the control group. CIMT was positively correlated with miR-29c (r=0.659, p< 0.001) and CRP (r=0.447, p< 0.001), and miR-29c levels were also correlated with CRP (r=0.512, p< 0.001). Furthermore, multiple linear regression analysis showed that CIMT was significantly correlated with miR-29c (β=0.573, 95% confidence interval [CI]: 0.315-0.839; p< 0.001) and CRP (β=0.439, 95%CI: 0.186–0.825; p< 0.001). After age, body mass index, systolic blood pressure, total cholesterol and fasting blood-glucose were adjusted for, CIMT was still closely associated with miR-29c (β=0.529, 95%CI: 0.354–0.812; p< 0.001) and CRP (β=0.417, 95%CI: 0.198–0.724; p< 0.001). Evaluating CRP and miR-29c together (AUC=0.900, p< 0.001) achieved a better prognostic value for atherosclerosis than miR-29c (AUC=0.870, p< 0.001) or CRP (AUC=0.722, p< 0.001) alone. Conclusion: Increased miR-29c was closely associated with CIMT and may serve as a biomarker for identifying atherosclerotic patients.

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Atherosclerosis-Associated Endothelial Cell Apoptosis by MiR-429-Mediated Down Regulation of Bcl-2

Cited by 50 publications

References 35 publications

Sildenafil (Viagra®) Prevents Cox-1/ TXA2 Pathway-Mediated Vascular Hypercontractility in ApoE-/- Mice

Sildenafil (Viagra®) Prevents Cox-1/ TXA2 Pathway-Mediated Vascular Hypercontractility in ApoE-/- Mice

MicroRNA-210 induces endothelial cell apoptosis by directly targeting PDK1 in the setting of atherosclerosis

Plasma MicroRNA-29c Levels Are Associated with Carotid Intima-Media Thickness and is a Potential Biomarker for the Early Detection of Atherosclerosis

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