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      Silencing of long non-coding RNA Sox2ot inhibits oxidative stress and inflammation of vascular smooth muscle cells in abdominal aortic aneurysm via microRNA-145-mediated Egr1 inhibition

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          Abstract

          Long non-coding RNAs (lncRNAs) have been largely reported to contribute to the development and progression of abdominal aortic aneurysm (AAA), a common vascular degenerative disease. The present study was set out with the aim to investigate the possible role of lncRNA Sox2ot in the development of AAA. In this study, we found that lncRNA Sox2ot and early growth response factor-1 (Egr1) were highly expressed, while microRNA (miR)-145 was poorly expressed in Ang II-induced AAA mice and oxidative stress-provoked vascular smooth muscle cell (VSMC) model. Egr1 was a potential target gene of miR-145, and lncRNA Sox2ot could competitively bind to miR-145 to upregulate Egr1 expression. Overexpression of miR-145-5p was found to attenuate oxidative stress and inflammation by inhibiting Egr1 both in vivo and in vitro, which was counteracted by lncRNA Sox2ot. Taken together, the present study provides evidence that downregulation of lncRNA Sox2ot suppressed the expression of Egr1 through regulating miR-145, thus inhibiting the development of AAA, highlighting a theoretical basis for AAA treatment.

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          Most cited references28

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          AMPKalpha2 deletion causes aberrant expression and activation of NAD(P)H oxidase and consequent endothelial dysfunction in vivo: role of 26S proteasomes.

          AMP-activated protein kinase (AMPK) is an energy sensor and ubiquitously expressed in vascular cells. Recent studies suggest that AMPK activation improves endothelial function by counteracting oxidative stress in endothelial cells. How AMPK suppresses oxidative stress remains to be established. The aim of this study is to examine the effects of AMPK in regulating NAD(P)H oxidase, oxidative stress, and endothelial function. The markers of oxidative stress, NAD(P)H oxidase subunit expression (gp91(phox), p47(phox), p67(phox), NOX1 to -4), NAD(P)H oxidase-mediated superoxide production, 26S proteasome activity, IkappaBalpha degradation, and nuclear translocation of nuclear factor (NF)-kappaB (p50 and p65) were examined in cultured human umbilical vein endothelial cells and mouse aortas isolated from AMPKalpha2 deficient mice. Compared to the wild type, acetylcholine-induced endothelium-dependent relaxation was significantly impaired in parallel with increased production of oxidants in AMPKalpha2(-/-) mice. Further, pretreatment of aorta with either superoxide dismutase (SOD) or tempol or apocynin significantly improved acetylcholine-induced endothelium-dependent relaxation in AMPKalpha2(-/-) mice. Analysis of aortic endothelial cells from AMPKalpha2(-/-) mice and human umbilical vein endothelial cells expressing dominant negative AMPK or AMPKalpha2-specific siRNA revealed that loss of AMPK activity increased NAD(P)H oxidase subunit expression (gp91(phox), p47(phox), p67(phox), NOX1 and -4), NAD(P)H oxidase-mediated superoxide production, 26S proteasome activity, IkappaBalpha degradation, and nuclear translocation of NF-kappaB (p50 and p65), whereas AMPK activation by AICAR or overexpression of constitutively active AMPK had the opposite effect. Consistently, we found that genetic deletion of AMPKalpha2 in low-density lipoprotein receptor knockout (LDLr(-/-)) strain markedly increased 26S proteasome activity, IkappaB degradation, NF-kappaB transactivation, NAD(P)H oxidase subunit overexpression, oxidative stress, and endothelial dysfunction, all of which were largely suppressed by chronic administration of MG132, a potent cell permeable proteasome inhibitor. We conclude that AMPKalpha2 functions as a physiological suppressor of NAD(P)H oxidase and ROS production in endothelial cells. In this way, AMPK maintains the nonatherogenic and noninflammatory phenotype of endothelial cells.
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            Decreased Expression of MicroRNA-143 and -145 in Human Gastric Cancers

            Objective: Downregulation of specific microRNAs (miRNAs) occurs in human tumors, which suggests a function for miRNAs in tumor suppression. We investigated the role of the miRNAs miR-143 and miR-145 in gastric cancers. Methods: The expression levels of miR-143 and miR-145 in the samples from 43 patients with gastric cancer were determined by real-time PCR using TaqMan assay. The growth inhibitory effect was estimated by the transfection of human gastric cancer cells with the miRNA. Results: The expression levels of miR-143 and -145 were decreased in most human gastric cancers examined, as previously reported to occur in colon tumors. The transfection of human gastric MKN-1 cells with miR-145 resulted in a greater growth inhibitory effect than that with miR-143, results which were contrary to those in colon cancers. In MKN-1 cells, an additive effect on growth inhibition was shown by the combined transfection with miR-143 and miR-145; further, higher sensitivity to 5-fluorouracil was also observed following the transfection with miR-143 or miR-145. The possible candidate target messenger RNAs of miR-145 were identified to be insulin receptor substrate-1 and β-actin. Conclusion: Taken together, these findings suggest that miR-143 and miR-145 act as anti-oncomirs common to gastrointestinal tumors.
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              MicroRNA-21 blocks abdominal aortic aneurysm development and nicotine-augmented expansion.

              Identification and treatment of abdominal aortic aneurysm (AAA) remains among the most prominent challenges in vascular medicine. MicroRNAs are crucial regulators of cardiovascular pathology and represent possible targets for the inhibition of AAA expansion. We identified microRNA-21 (miR-21) as a key modulator of proliferation and apoptosis of vascular wall smooth muscle cells during development of AAA in two established murine models. In both models (AAA induced by porcine pancreatic elastase or infusion of angiotensin II), miR-21 expression increased as AAA developed. Lentiviral overexpression of miR-21 induced cell proliferation and decreased apoptosis in the aortic wall, with protective effects on aneurysm expansion. miR-21 overexpression substantially decreased expression of the phosphatase and tensin homolog (PTEN) protein, leading to increased phosphorylation and activation of AKT, a component of a pro-proliferative and antiapoptotic pathway. Systemic injection of a locked nucleic acid-modified antagomir targeting miR-21 diminished the pro-proliferative impact of down-regulated PTEN, leading to a marked increase in the size of AAA. Similar results were seen in mice with AAA augmented by nicotine and in human aortic tissue samples from patients undergoing surgical repair of AAA (with more pronounced effects observed in smokers). Modulation of miR-21 expression shows potential as a new therapeutic option to limit AAA expansion and vascular disease progression.
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                Author and article information

                Journal
                Aging (Albany NY)
                Aging (Albany NY)
                Aging
                Aging (Albany NY)
                Impact Journals
                1945-4589
                15 July 2020
                06 July 2020
                : 12
                : 13
                : 12684-12702
                Affiliations
                [1 ]Department of Cardiovascular Surgery, Provincial Clinical College of Fujian Medical University, Fujian Provincial Hospital, Fuzhou 350001, P.R. China
                [2 ]Department of Cardiology, Provincial Clinical College of Fujian Medical University, Fujian Provincial Hospital, Fuzhou 350001, P.R. China
                [3 ]Department of Imaging, Provincial Clinical College of Fujian Medical University, Fujian Provincial Hospital, Fuzhou 350001, P.R. China
                Author notes
                [*]

                Co-first authors

                Correspondence to: Ren Wang; email: wangrenfw@163.com
                Article
                103077 103077
                10.18632/aging.103077
                7377859
                32629426
                59858e8b-a940-4872-b107-79c0b4b3c2ee
                Copyright © 2020 Lin et al.

                This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                History
                : 26 September 2019
                : 29 March 2020
                Categories
                Research Paper

                Cell biology
                long non-coding rna sox2ot,microrna-145,egr1,abdominal aortic aneurysm,oxidative stress

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