MicroRNA‑15b participates in the development of peripheral arterial disease by modulating the growth of vascular smooth muscle cells

Sun,Yong; Gao,Yong; Song,Tao; Yu,Chaowen; Nie ,Zhonglin; Wang,Xiaogao

doi:10.3892/etm.2019.7552

MicroRNA‑15b participates in the development of peripheral arterial disease by modulating the growth of vascular smooth muscle cells

Authors:
- Yong Sun
- Yong Gao
- Tao Song
- Chaowen Yu
- Zhonglin Nie
- Xiaogao Wang
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Affiliations: Department of Vascular Surgery, The First Affiliated Hospital of Bengbu Medical College, Bengbu, Anhui 233004, P.R. China
Published online on: May 7, 2019 https://doi.org/10.3892/etm.2019.7552
Pages: 77-84
Copyright: © Sun et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

As an atherosclerotic disease, the process of peripheral arterial disease (PAD) is complicated and includes the abnormal proliferation of vascular smooth muscle. The current study aimed to determine the role of microRNA‑15b (miR‑15b) in the development of PAD and its associated mechanisms. Human vascular smooth muscle cells (hVSMCs) were used in the current study. To assess the effects of miR‑15b on hVSMCs, miR‑15b was up‑ or downregulated in hVSMCs using miR‑15b mimics or miR‑15b inhibitors respectively. Cell viability, migration and apoptosis were then determined via MTT, transwell and flow cytometry assays, respectively. TargetScan bioinformatics software was utilized to predict the targets of miR‑15b, and the binding sites between insulin growth factor 1 receptor (IGF1R) and miR‑15b were confirmed by dual‑luciferase reporter assay. The results reveled that the miR‑15b mimic significantly reduced hVSMC cell viability and migration, and promoted cell apoptosis. However, the opposite effect was observed following miR‑15b inhibitor transfection. It was also determined that miR‑15b directly targeted IGF1R and negatively regulated its expression in hVSMCs. Additionally, the results demonstrated that the miR‑15b mimic inhibited the PI3K/AKT signaling pathway in hVSMCs, whereas the miR‑15b inhibitor promoted it. Furthermore, the results indicated that the effect of the miR‑15b mimic on hVSMCs was reversed by IGF1R overexpression. In conclusion, the data indicated that miR‑15b participated in the occurrence and development of PAD by modulating hVSMC proliferation, apoptosis and migration via the regulation of IGF1R expression.

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1	Stather PW, Sylvius N, Wild JB, Choke E, Sayers RD and Bown MJ: Differential microRNA expression profiles in peripheral arterial disease. Circ Cardiovasc Genet. 6:490–497. 2013. View Article : Google Scholar : PubMed/NCBI
2	Togliatto G, Trombetta A, Dentelli P, Gallo S, Rosso A, Cotogni P, Granata R, Falcioni R, Delale T, Ghigo E and Brizzi MF: Unacylated ghrelin induces oxidative stress resistance in a glucose intolerance and peripheral artery disease mouse model by restoring endothelial cell miR-126 expression. Diabetes. 64:1370–1382. 2015. View Article : Google Scholar : PubMed/NCBI
3	Chen L, Liu C, Sun D, Wang T, Zhao L, Chen W, Yuan M, Wang J and Lu W: MicroRNA-133a impairs perfusion recovery after hindlimb ischemia in diabetic mice. Biosci Rep. 38:BSR201803462018. View Article : Google Scholar : PubMed/NCBI
4	Hsu PY, Hsi E, Wang TM, Lin RT, Liao YC and Juo SH: MicroRNA let-7g possesses a therapeutic potential for peripheral artery disease. J Cell Mol Me. 21:519–529. 2017. View Article : Google Scholar
5	Dua A and Lee CJ: Epidemiology of peripheral arterial disease and critical limb ischemia. Tech Vasc Interv Radiol. 19:91–95. 2016. View Article : Google Scholar : PubMed/NCBI
6	Abu Dabrh AM, Steffen MW, Undavalli C, Asi N, Wang Z, Elamin MB, Conte MS and Murad MH: The natural history of untreated severe or critical limb ischemia. J Vasc Surg. 62:1642–1651.e3. 2015. View Article : Google Scholar : PubMed/NCBI
7	Rollins KE, Jackson D and Coughlin PA: Meta-analysis of contemporary short- and long-term mortality rates in patients diagnosed with critical leg ischaemia. Br J Surg. 100:1002–1008. 2013. View Article : Google Scholar : PubMed/NCBI
8	Mejias SG and Ramphul K: Prevalence of peripheral arterial disease among diabetic patients in Santo Domingo, Dominican Republic and associated risk factors. Arch Med Sci Atheroscler Dis. 3:e35–e40. 2018. View Article : Google Scholar : PubMed/NCBI
9	Kloos W, Vogel B and Blessing E: MiRNAs in peripheral artery disease-something gripping this way comes. Vasa. 43:163–170. 2014. View Article : Google Scholar : PubMed/NCBI
10	Ganta VC, Choi MH, Kutateladze A, Fox TE, Farber CR and Annex BH: A MicroRNA93-interferon regulatory factor-9-immunoresponsive gene-1-itaconic acid pathway modulates M2-like macrophage polarization to revascularize ischemic muscle. Circulation. 135:2403–2425. 2017. View Article : Google Scholar : PubMed/NCBI
11	Fang J, Song XW, Tian J, Chen HY, Li DF, Wang JF, Ren AJ, Yuan WJ and Lin L: Overexpression of microRNA-378 attenuates ischemia-induced apoptosis by inhibiting caspase-3 expression in cardiac myocytes. Apoptosis. 17:410–423. 2012. View Article : Google Scholar : PubMed/NCBI
12	Zhou X, Yuan P and He Y: Role of microRNAs in peripheral artery disease (review). Mol Med Rep. 6:695–700. 2012. View Article : Google Scholar : PubMed/NCBI
13	Zampetaki A and Mayr M: MicroRNAs in vascular and metabolic disease. Circ Res. 110:508–522. 2012. View Article : Google Scholar : PubMed/NCBI
14	Shantikumar S, Caporali A and Emanueli C: Role of microRNAs in diabetes and its cardiovascular complications. Cardiovasc Res. 93:583–593. 2012. View Article : Google Scholar : PubMed/NCBI
15	Katare R, Riu F, Mitchell K, Gubernator M, Campagnolo P, Cui Y, Fortunato O, Avolio E, Cesselli D, Beltrami AP, et al: Transplantation of human pericyte progenitor cells improves the repair of infarcted heart through activation of an angiogenic program involving micro-RNA-132. Circ Res. 109:894–906. 2011. View Article : Google Scholar : PubMed/NCBI
16	Livak KJ and Schmittgen TD: Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) method. Methods. 25:402–408. 2001. View Article : Google Scholar : PubMed/NCBI
17	Paraskevas KI, Kotsikoris I, Koupidis SA, Giannoukas AD and Mikhailidis DP: Ankle-brachial index: A marker of both peripheral arterial disease and systemic atherosclerosis as well as a predictor of vascular events. Angiology. 61:521–523. 2010. View Article : Google Scholar : PubMed/NCBI
18	Wu MY, Li CJ, Hou MF and Chu PY: New insights into the role of inflammation in the pathogenesis of atherosclerosis. Int J Mol Sci. 18:E20342017. View Article : Google Scholar : PubMed/NCBI
19	Di Pietro N, Formoso G and Pandolfi A: Physiology and pathophysiology of oxLDL uptake by vascular wall cells in atherosclerosis. Vascul Pharmacol. 84:1–7. 2016. View Article : Google Scholar : PubMed/NCBI
20	Fu S, Zhao H, Shi J, Abzhanov A, Crawford K, Ohno-Machado L, Zhou J, Du Y, Kuo WP, Zhang J, et al: Peripheral arterial occlusive disease: Global gene expression analyses suggest a major role for immune and inflammatory responses. BMC Genomics. 9:3692008. View Article : Google Scholar : PubMed/NCBI
21	Wingrove JA, Daniels SE, Sehnert AJ, Tingley W, Elashoff MR, Rosenberg S, Buellesfeld L, Grube E, Newby LK, Ginsburg GS and Kraus WE: Correlation of peripheral-blood gene expression with the extent of coronary artery stenosis. Circ Cardiovasc Genet. 1:31–38. 2008. View Article : Google Scholar : PubMed/NCBI
22	Masud R, Shameer K, Dhar A, Ding K and Kullo IJ: Gene expression profling of peripheral blood mononuclear cells in the setting of peripheral arterial disease. J Clin Bioinforma. 2:62012. View Article : Google Scholar : PubMed/NCBI
23	Wang B, Hong W and Yang Z: MiR-122 inhibits cell proliferation and tumorigenesis of breast cancer by targeting IGF1R. PLoS One. 7:e470532012. View Article : Google Scholar : PubMed/NCBI
24	Li J and Wang H: miR-15b reduces amyloid-β accumulation in SH-SY5Y cell line through targeting NF-κB signaling and BACE1. Biosci Rep. 38:BSR201800512018. View Article : Google Scholar : PubMed/NCBI
25	Sun G, Yan S, Shi L, Wan Z, Jiang N, Li M and Guo J: Decreased expression of miR-15b in human gliomas is associated with poor prognosis. Cancer Biother Radiopharm. 30:169–173. 2015. View Article : Google Scholar : PubMed/NCBI
26	Wang H, Zhan Y, Jin J, Zhang C and Li W: MicroRNA-15b promotes proliferation and invasion of non-small cell lung carcinoma cells by directly targeting TIMP2. Oncol Rep. 37:3305–3312. 2017. View Article : Google Scholar : PubMed/NCBI
27	Kang L, Yang C, Yin H, Zhao K, Liu W, Hua W, Wang K, Song Y, Tu J, Li S, et al: MicroRNA-15b silencing inhibits IL-1β-induced extracellular matrix degradation by targeting SMAD3 in human nucleus pulposus cells. Biotechnol Lett. 39:623–632. 2017. View Article : Google Scholar : PubMed/NCBI
28	Solarek W, Czarnecka AM, Escudier B, Bielecka ZF, Lian F and Szczylik C: Insulin and IGFs in renal cancer risk and progression. Endocr Relat Cancer. 22:R253–R264. 2015. View Article : Google Scholar : PubMed/NCBI
29	Pollak M: The insulin and insulin-like growth factor receptor family in neoplasia: An update. Nat Rev Cancer. 12:159–169. 2012. View Article : Google Scholar : PubMed/NCBI