MiRNA-146a regulates the maturation and differentiation of vascular smooth muscle cells by targeting NF-κB expression

Dong,Shaohong; Xiong,Wei; Yuan,Jianhui; Li,Jianghua; Liu,Jianjun; Xu,Xinyun

doi:10.3892/mmr.2013.1538

MiRNA-146a regulates the maturation and differentiation of vascular smooth muscle cells by targeting NF-κB expression

Authors:
- Shaohong Dong
- Wei Xiong
- Jianhui Yuan
- Jianghua Li
- Jianjun Liu
- Xinyun Xu
View Affiliations

Affiliations: Department of Cardiology, The Second Clinical Medical College of Jinan University, Shenzhen People's Hospital, Shenzhen, Guangdong 518020, P.R. China, Key Laboratory of Modern Toxicology of Shenzhen, Shenzhen Center for Disease Control and Prevention, Shenzhen, Guangdong 518055, P.R. China
Published online on: June 20, 2013 https://doi.org/10.3892/mmr.2013.1538
Pages: 407-412

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

Dysfunction of vascular smooth muscle cells (VSMCs) is key in the pathogenesis of proliferative cardiovascular diseases, including atherosclerosis and post-angioplasty restenosis. However, to date, the molecular mechanisms of this pathological process have not been elucidated. Growing evidence indicates that microRNAs (miRNAs) are a class of novel gene regulators. Recently, miR-146a was shown to be highly expressed in rat balloon-injured vascular walls as well as in peripheral blood mononuclear cells (PBMCs) from patients with acute coronary syndrome (ACS). The aim of the present study was to investigate the role of miR-146a in regulating VSMC fate and the possible underlying mechanisms involved. Our results revealed that the expression of miR‑146a was increased in proliferative VSMCs. Subsequently, we observed that the knockdown of miR‑146a significantly inhibited the proliferative and migratory properties of VSMCs in vitro, while it markedly promoted the apoptotic capacity of VSMCs. In addition, we demonstrated that the protein expression of nuclear factor-κBp65 (NF-κBp65) and the proliferative cell nuclear antigen (PCNA), known as critical transcriptional factors, were downregulated. By contrast, the crucial proapoptotic molecule Bax has been revealed to be upregulated following miR‑146a knockdown. These results support the conclusion that miR-146a is a novel regulator of VSMC fate and may be a new biomarker or therapeutic target for proliferative cardiovascular disease.

View Figures

View References

1	Owens GK, Kumar MS and Wamhoff BR: Molecular regulation of vascular smooth muscle cell differentiation in development and disease. Physiol Rev. 84:767–801. 2004. View Article : Google Scholar : PubMed/NCBI
2	Rzucidlo EM, Martin KA and Powell RJ: Regulation of vascular smooth muscle cell differentiation. J Vasc Surg. 45:A25–A32. 2007. View Article : Google Scholar : PubMed/NCBI
3	Reinhart BJ, Slack FJ, Basson M, Pasquinelli AE, Bettinger JC, Rougvie AE, Horvitz HR and Ruvkun G: The 21-nucleotide let-7 RNA regulates developmental timing in Caenorhabditis elegans. Nature. 403:901–906. 2000. View Article : Google Scholar : PubMed/NCBI
4	Pasquinelli AE, Reinhart BJ, Slack F, Martindale MQ, Kuroda MI, Maller B, Hayward DC, Ball EE, Degnan B, Müller P, Spring J, Srinivasan A, Fishman M, Finnerty J, Corbo J, Levine M, Leahy P, Davidson E and Ruvkun G: Conservation of the sequence and temporal expression of let-7 heterochronic regulatory RNA. Nature. 408:86–89. 2000. View Article : Google Scholar : PubMed/NCBI
5	Lee RC and Ambros V: An extensive class of small RNAs in Caenorhabditis elegans. Science. 294:862–864. 2001. View Article : Google Scholar : PubMed/NCBI
6	Zhao Y, Ransom JF, Li A, Vedantham V, von Drehle M, Muth AN, Tsuchihashi T, McManus MT, Schwartz RJ and Srivastava D: Serum response factor regulates a muscle-specific microRNA that targets Hand2 during cardiogenesis. Nature. 436:214–220. 2005. View Article : Google Scholar : PubMed/NCBI
7	Zhao Y, Ransom JF, Li A, Vedantham V, von Drehle M, Muth AN, Tsuchihashi T, McManus MT, Schwartz RJ and Srivastava D: Dysregulation of cardiogenesis, cardiac conduction, and cell cycle in mice lacking miRNA-1-2. Cell. 129:303–317. 2007. View Article : Google Scholar : PubMed/NCBI
8	Sayed D, Hong C, Chen IY, Lypowy J and Abdellatif M: MicroRNAs play an essential role in the development of cardiac hypertrophy. Circ Res. 100:416–424. 2007. View Article : Google Scholar : PubMed/NCBI
9	Yang B, Lin H, Xiao J, Lu Y, Luo X, Li B, Zhang Y, Xu C, Bai Y, Wang H, Chen G and Wang Z: The muscle-specific microRNA miR-1 regulates cardiac arrhythmogenic potential by targeting GJA1 and KCNJ2. Nat Med. 13:486–491. 2007. View Article : Google Scholar : PubMed/NCBI
10	Yang B, Lin H, Xiao J, Lu Y, Luo X, Li B, Zhang Y, Xu C, Bai Y, Wang H, Chen G and Wang Z: MicroRNAs in the human heart: a clue to fetal gene reprogramming in heart failure. Circulation. 116:258–267. 2007. View Article : Google Scholar : PubMed/NCBI
11	Ji R, Cheng Y, Yue J, Yang J, Liu X, Chen H, Dean DB and Zhang C: MicroRNA expression signature and antisense-mediated depletion reveal an essential role of microRNA in vascular neointimal lesion formation. Circ Res. 100:1579–1588. 2007. View Article : Google Scholar : PubMed/NCBI
12	Taganov KD, Boldin MP, Chang KJ and Baltimore D: NF-κB dependent induction of microRNA miR-146a, an inhibitor targeted to signaling proteins of innate immune responses. Proc Natl Acad Sci USA. 103:12481–12486. 2006.
13	Bandiera S, Hatem E, Lyonnet S and Henrion-Caude A: microRNAs in diseases: from candidate to modifier genes. Clin Genet. 77:306–313. 2010. View Article : Google Scholar : PubMed/NCBI
14	Esteller M: Non-coding RNAs in human disease. Nat Rev Genet. 12:861–874. 2011. View Article : Google Scholar
15	Kaikkonen MU, Lam MT and Glass CK: Non-coding RNAs as regulators of gene expression and epigenetics. Cardiovasc Res. 90:430–440. 2011. View Article : Google Scholar : PubMed/NCBI
16	Fichtlscherer S, Zeiher AM and Dimmeler S: Circulating microRNAs: biomarkers or mediators of cardiovascular diseases? Arterioscler Thromb Vasc Biol. 31:2383–2390. 2011. View Article : Google Scholar : PubMed/NCBI
17	Nahid MA, Pauley KM, Satoh M and Chan EK: miR-146a is critical for endotoxin-induced tolerance: implication in innate immunity. J Biol Chem. 284:34590–34599. 2009. View Article : Google Scholar : PubMed/NCBI
18	Jurkin J, Schichl YM, Koeffel R, Bauer T, Richter S, Konradi S, Gesslbauer B and Strobl H: miR-146a is differentially expressed by myeloid dendritic cell subsets and desensitizes cells to TLR2-dependent activation. J Immunol. 184:4955–4965. 2010. View Article : Google Scholar : PubMed/NCBI
19	Lu LF, Boldin MP, Chaudhry A, Lin LL, Taganov KD, Hanada T, Yoshimura A, Baltimore D and Rudensky AY: Function of miR-146a in controlling treg cell-mediated regulation of Th1 responses. Cell. 142:914–929. 2010. View Article : Google Scholar : PubMed/NCBI
20	He H, Jazdzewski K, Li W, Liyanarachchi S, Nagy R, Volinia S, Calin GA, Liu CG, Franssila K, Suster S, Kloos RT, Croce CM and de la Chapelle A: The role of microRNA genes in papillary thyroid carcinoma. Proc Natl Acad Sci USA. 102:19075–19080. 2005. View Article : Google Scholar : PubMed/NCBI
21	Bhaumik D, Scott GK, Schokrpur S, Patil CK, Campisi J and Benz CC: Expression of microRNA-146 suppresses NF-κB activity with reduction of metastatic potential in breast cancer cells. Oncogene. 27:5643–5647. 2008.PubMed/NCBI
22	Li Y, Vandenboom TG 2nd, Wang Z, Kong D, Ali S, Philip PA and Sarkar FH: miR-146a suppresses invasion of pancreatic cancer cells. Cancer Res. 70:1486–1495. 2010. View Article : Google Scholar : PubMed/NCBI
23	Cameron JE, Yin Q, Fewell C, Lacey M, McBride J, Wang X, Lin Z, Schaefer BC and Flemington EK: Epstein-Barr virus latent membrane protein 1 induces cellular microRNA miR-146a, a modulator of lymphocyte signaling pathways. J Virol. 82:1946–1958. 2008. View Article : Google Scholar : PubMed/NCBI
24	Liu G, Friggeri A, Yang Y, Park YJ, Tsuruta Y and Abraham E: miR-147, a microRNA that is induced upon toll-like receptor stimulation, regulates murine macrophage inflammatory responses. Proc Natl Acad Sci USA. 106:15819–15824. 2009. View Article : Google Scholar : PubMed/NCBI
25	Pauley KM, Satoh M, Chan AL, Bubb MR, Reeves WH and Chan EK: Upregulated miR-146a expression in peripheral blood mononuclear cells from rheumatoid arthritis patients. Arthritis Res Ther. 10:R1012008. View Article : Google Scholar : PubMed/NCBI
26	Nakasa T, Miyaki S, Okubo A, Hashimoto M, Nishida K, Ochi M and Asahara H: Expression of microRNA-146 in rheumatoid arthritis synovial tissue. Arthritis Rheum. 58:1284–1292. 2008. View Article : Google Scholar : PubMed/NCBI
27	Perry MM, Moschos SA, Williams AE, Shepherd NJ, Larner-Svensson HM and Lindsay MA: Rapid changes in microrna-146a expression negatively regulate the IL-1β-induced inflammatory response in human lung alveolar epithelial cells1. J Immunol. 180:5689–5698. 2008.PubMed/NCBI
28	Cordes KR, Sheehy NT, White MP, Berry EC, Morton SU, Muth AN, Lee TH, Miano JM, Ivey KN and Srivastava D: miR-145 and miR-143 regulate smooth muscle cell fate and plasticity. Nature. 460:705–710. 2009.PubMed/NCBI
29	Davis BN, Hilyard AC, Nguyen PH, Lagna G and Hata A: Induction of microRNA-221 by platelet-derived growth factor signaling is critical for modulation of vascular smooth muscle phenotype. J Biol Chem. 284:3728–3738. 2009. View Article : Google Scholar : PubMed/NCBI
30	Guo M, Mao X, Ji Q, Lang M, Li S, Peng Y, Zhou W, Xiong B and Zeng Q: miR-146a in PBMCs modulates Th1 function in patients with acute coronary syndrome. Immunol Cell Biol. 88:555–564. 2010. View Article : Google Scholar : PubMed/NCBI
31	Lalier L, Cartron PF, Juin P, Nedelkina S, Manon S, Bechinger B and Vallette FM: Bax activation and mitochondrial insertion during apoptosis. Apoptosis. 12:887–896. 2007. View Article : Google Scholar : PubMed/NCBI