Proliferation of vascular smooth muscle cells under inflammation is regulated by NF-κB p65/microRNA-17/RB pathway activation

Yang,Dong; Sun,Chen; Zhang,Jing; Lin,Shu; Zhao,Lin; Wang,Lun; Lin,Ruoran; Lv,Junyuan; Xin,Shijie

doi:10.3892/ijmm.2017.3212

Proliferation of vascular smooth muscle cells under inflammation is regulated by NF-κB p65/microRNA-17/RB pathway activation

Authors:
- Dong Yang
- Chen Sun
- Jing Zhang
- Shu Lin
- Lin Zhao
- Lun Wang
- Ruoran Lin
- Junyuan Lv
- Shijie Xin
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Affiliations: Department of Vascular Surgery, The First Affiliated Hospital of China Medical University, Shenyang, Liaoning 110001, P.R. China, Department of Pharmacology, School of Pharmacy, China Medical University, Shenyang, Liaoning 110122, P.R. China
Published online on: October 25, 2017 https://doi.org/10.3892/ijmm.2017.3212
Pages: 43-50
Copyright: © Yang et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

Inflammation and excessive proliferation of vascular smooth muscle cells (VSMCs) have key roles in various vascular disorders, including restenosis, atherosclerosis and pulmonary artery hypertension. However, the underlying mechanism remains unclear. The present study investigated the role of nuclear factor-κB (NF-κB) and microRNA (miRNA) in the regulation of VSMC proliferation under inflammatory conditions. It was demonstrated that miR‑17 stimulated the proliferation of VSMCs, enhanced cell cycle G1/S transition, and increased levels of proliferating cell nuclear antigen and E2F1. By directly targeting the retinoblastoma (RB) protein mRNA-3' untranslated region, miR‑17 suppressed the expression of RB. Activation of NF-κB p65 resulted in increased miR‑17 expression in VSMCs, whereas inactivation of NF-κB p65 resulted in decreased expression of miR‑17 in VSMCs. NF-κB p65 signalling directly regulates miR‑17 promoter activity. NF-κB p65 activation also suppressed RB expression, which was abrogated by miR‑17 inhibitor. Taken together, the present results indicated that VSMC proliferation is regulated by activation of the NF-κB p65/miR‑17/RB pathway. As NF-κB p65 signalling is activated in and is a master regulator of the inflammatory response, the present findings may provide a mechanism for the excessive proliferation of VSMCs under inflammation during vascular disorders and may identify novel targets for the treatment of vascular diseases.

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1	Bauters C and Isner JM: The biology of restenosis. Prog Cardiovasc Dis. 40:107–116. 1997. View Article : Google Scholar : PubMed/NCBI
2	Yahagi K, Otsuka F, Sakakura K, Sanchez OD, Kutys R, Ladich E, Kolodgie FD, Virmani R and Joner M: Pathophysiology of superficial femoral artery in-stent restenosis. J Cardiovasc Surg Torino: 55. pp. 307–323. 2014
3	McNamara CA, Sarembock IJ, Bachhuber BG, Stouffer GA, Ragosta M, Barry W, Gimple LW, Powers ER and Owens GK: Thrombin and vascular smooth muscle cell proliferation: Implications for atherosclerosis and restenosis. Semin Thromb Hemost. 22:139–144. 1996. View Article : Google Scholar : PubMed/NCBI
4	Sheikh AQ, Lighthouse JK and Greif DM: Recapitulation of developing artery muscularization in pulmonary hypertension. Cell Reports. 6:809–817. 2014. View Article : Google Scholar : PubMed/NCBI
5	Satoh K, Satoh T, Kikuchi N, Omura J, Kurosawa R, Suzuki K, Sugimura K, Aoki T, Nochioka K, Tatebe S, et al: Basigin mediates pulmonary hypertension by promoting inflammation and vascular smooth muscle cell proliferation. Circ Res. 115:738–750. 2014. View Article : Google Scholar : PubMed/NCBI
6	Donners MM, Daemen MJ, Cleutjens KB and Heeneman S: Inflammation and restenosis: Implications for therapy. Ann Med. 35:523–531. 2003. View Article : Google Scholar : PubMed/NCBI
7	Drachman DE and Simon DI: Inflammation as a mechanism and therapeutic target for in-stent restenosis. Curr Atheroscler Rep. 7:44–49. 2005. View Article : Google Scholar : PubMed/NCBI
8	Schillinger M and Minar E: Restenosis after percutaneous angioplasty: The role of vascular inflammation. Vasc Health Risk Manag. 1:73–78. 2005. View Article : Google Scholar
9	Tanaskovic S, Isenovic ER and Radak D: Inflammation as a marker for the prediction of internal carotid artery restenosis following eversion endarterectomy - evidence from clinical studies. Angiology. 62:535–542. 2011. View Article : Google Scholar : PubMed/NCBI
10	Parker M, Mohankumar KM, Punchihewa C, Weinlich R, Dalton JD, Li Y, Lee R, Tatevossian RG, Phoenix TN, Thiruvenkatam R, et al: C11orf95-RELA fusions drive oncogenic NF-κB signalling in ependymoma. Nature. 506:451–455. 2014. View Article : Google Scholar : PubMed/NCBI
11	Suzuki J, Tezuka D, Morishita R and Isobe M: An initial case of suppressed restenosis with nuclear factor-kappa B decoy transfection after percutaneous coronary intervention. J Gene Med. 11:89–91. 2009. View Article : Google Scholar
12	Ohtani K, Egashira K, Nakano K, Zhao G, Funakoshi K, Ihara Y, Kimura S, Tominaga R, Morishita R and Sunagawa K: Stent-based local delivery of nuclear factor-kappaB decoy attenuates in-stent restenosis in hypercholesterolemic rabbits. Circulation. 114:2773–2779. 2006. View Article : Google Scholar : PubMed/NCBI
13	Beitzinger M and Meister G: Preview. MicroRNAs: From decay to decoy. Cell. 140:612–614. 2010. View Article : Google Scholar : PubMed/NCBI
14	Gareri C, De Rosa S and Indolfi C: MicroRNAs for restenosis and thrombosis after vascular injury. Circ Res. 118:1170–1184. 2016. View Article : Google Scholar : PubMed/NCBI
15	Lv J, Wang L, Zhang J, Lin R, Wang L, Sun W, Wu H and Xin S: Long noncoding RNA H19-derived miR-675 aggravates restenosis by targeting PTEN. Biochem Biophys Res Commun: Jan. 4:2017Epub ahead of print. View Article : Google Scholar
16	Stein JJ, Iwuchukwu C, Maier KG and Gahtan V: Thrombospondin-1-induced vascular smooth muscle cell migration and proliferation are functionally dependent on microRNA-21. Surgery. 155:228–233. 2014. View Article : Google Scholar
17	Li Y, Yan L, Zhang W, Hu N, Chen W, Wang H, Kang M and Ou H: MicroRNA-21 inhibits platelet-derived growth factor-induced human aortic vascular smooth muscle cell proliferation and migration through targeting activator protein-1. Am J Transl Res. 6:507–516. 2014.PubMed/NCBI
18	Muthiah M, Islam MA, Cho CS, Hwang JE, Chung IJ and Park IK: Substrate-mediated delivery of microRNA-145 through a polysorbitol-based osmotically active transporter suppresses smooth muscle cell proliferation: Implications for restenosis treatment. J Biomed Nanotechnol. 10:571–579. 2014. View Article : Google Scholar : PubMed/NCBI
19	Santulli G, Wronska A, Uryu K, Diacovo TG, Gao M, Marx SO, Kitajewski J, Chilton JM, Akat KM, Tuschl T, et al: A selective microRNA-based strategy inhibits restenosis while preserving endothelial function. J Clin Invest. 124:4102–4114. 2014. View Article : Google Scholar : PubMed/NCBI
20	Mogilyansky E and Rigoutsos I: The miR-17/92 cluster: A comprehensive update on its genomics, genetics, functions and increasingly important and numerous roles in health and disease. Cell Death Differ. 20:1603–1614. 2013. View Article : Google Scholar : PubMed/NCBI
21	Mendell JT: miRiad roles for the miR-17-92 cluster in development and disease. Cell. 133:217–222. 2008. View Article : Google Scholar : PubMed/NCBI
22	Chen Z, Wu J, Yang C, Fan P, Balazs L, Jiao Y, Lu M, Gu W, Li C, Pfeffer LM, et al: DiGeorge syndrome critical region 8 (DGCR8) protein-mediated microRNA biogenesis is essential for vascular smooth muscle cell development in mice. J Biol Chem. 287:19018–19028. 2012. View Article : Google Scholar : PubMed/NCBI
23	Luo T, Cui S, Bian C and Yu X: Crosstalk between TGF-β/Smad3 and BMP/BMPR2 signaling pathways via miR-17-92 cluster in carotid artery restenosis. Mol Cell Biochem. 389:169–176. 2014. View Article : Google Scholar : PubMed/NCBI
24	Maier KG, Ruhle B, Stein JJ, Gentile KL, Middleton FA and Gahtan V: Thrombospondin-1 differentially regulates microRNAs in vascular smooth muscle cells. Mol Cell Biochem. 412:111–117. 2016. View Article : Google Scholar : PubMed/NCBI
25	Weinberg RA: The retinoblastoma protein and cell cycle control. Cell. 81:323–330. 1995. View Article : Google Scholar : PubMed/NCBI
26	Burke JR, Hura GL and Rubin SM: Structures of inactive retinoblastoma protein reveal multiple mechanisms for cell cycle control. Genes Dev. 26:1156–1166. 2012. View Article : Google Scholar : PubMed/NCBI
27	Livak KJ and Schmittgen TD: Analysis of relative gene expression data using real-time quantitative PCR and the 2(−ΔΔC(T)) method. Methods. 25:402–408. 2001. View Article : Google Scholar
28	Shi J, Bei Y, Kong X, Liu X, Lei Z, Xu T, Wang H, Xuan Q, Chen P, Xu J, et al: miR-17-3p contributes to exercise-induced cardiac growth and protects against myocardial ischemia-reperfusion injury. Theranostics. 7:664–676. 2017. View Article : Google Scholar : PubMed/NCBI
29	Chen T, Zhou Q, Tang H, Bozkanat M, Yuan JX, Raj JU and Zhou G: miR-17/20 controls prolyl hydroxylase 2 (HD2)/hypoxia-inducible factor 1 (HIF1) to regulate pulmonary artery smooth muscle cell proliferation. J Am Heart Assoc. 5:e0045102016. View Article : Google Scholar
30	Blais A and Dynlacht BD: Hitting their targets: An emerging picture of E2F and cell cycle control. Curr Opin Genet Dev. 14:527–532. 2004. View Article : Google Scholar : PubMed/NCBI
31	Wong JV, Dong P, Nevins JR, Mathey-Prevot B and You L: Network calisthenics: Control of E2F dynamics in cell cycle entry. Cell Cycle. 10:3086–3094. 2011. View Article : Google Scholar : PubMed/NCBI
32	Essers J, Theil AF, Baldeyron C, van Cappellen WA, Houtsmuller AB, Kanaar R and Vermeulen W: Nuclear dynamics of PCNA in DNA replication and repair. Mol Cell Biol. 25:9350–9359. 2005. View Article : Google Scholar : PubMed/NCBI
33	Fischer M and Müller GA: Cell cycle transcription control: DREAM/MuvB and RB-E2F complexes. Crit Rev Biochem Mol Biol. Aug 11–2017.Epub ahead of print. View Article : Google Scholar : PubMed/NCBI
34	Korenjak M and Brehm A: E2F-Rb complexes regulating transcription of genes important for differentiation and development. Curr Opin Genet Dev. 15:520–527. 2005. View Article : Google Scholar : PubMed/NCBI
35	Schaal C, Pillai S and Chellappan SP: The Rb-E2F transcriptional regulatory pathway in tumor angiogenesis and metastasis. Adv Cancer Res. 121:147–182. 2014. View Article : Google Scholar : PubMed/NCBI
36	Giangrande PH, Zhang J, Tanner A, Eckhart AD, Rempel RE, Andrechek ER, Layzer JM, Keys JR, Hagen PO, Nevins JR, et al: Distinct roles of E2F proteins in vascular smooth muscle cell proliferation and intimal hyperplasia. Proc Natl Acad Sci USA. 104:12988–12993. 2007. View Article : Google Scholar : PubMed/NCBI
37	Araki K, Kawauchi K and Tanaka N: IKK/NF-kappaB signaling pathway inhibits cell-cycle progression by a novel Rb-independent suppression system for E2F transcription factors. Oncogene. 27:5696–5705. 2008. View Article : Google Scholar : PubMed/NCBI
38	Kravtsova-Ivantsiv Y, Shomer I, Cohen-Kaplan V, Snijder B, Superti-Furga G, Gonen H, Sommer T, Ziv T, Admon A, Naroditsky I, et al: KPC1-mediated ubiquitination and proteasomal processing of NF-κB1 105 to 50 restricts tumor growth. Cell. 161:333–347. 2015. View Article : Google Scholar : PubMed/NCBI
39	Zhang X, Liu S, Hu T, Liu S, He Y and Sun S: Up-regulated microRNA-143 transcribed by nuclear factor kappa B enhances hepatocarcinoma metastasis by repressing fibronectin expression. Hepatology. 50:490–499. 2009. View Article : Google Scholar : PubMed/NCBI