Upregulated microRNA-214 enhances cardiac injury by targeting ITCH during coxsackievirus infection

Chen,Zhi‑Gang; Liu,Hui; Zhang,Jun‑Biao; Zhang,Shao‑Li; Zhao,Li‑Hua; Liang,Wan‑Qian

doi:10.3892/mmr.2015.3539

Upregulated microRNA-214 enhances cardiac injury by targeting ITCH during coxsackievirus infection

Authors:
- Zhi‑Gang Chen
- Hui Liu
- Jun‑Biao Zhang
- Shao‑Li Zhang
- Li‑Hua Zhao
- Wan‑Qian Liang
View Affiliations

Affiliations: Department of Cardiovascular Medicine, The First Affiliated Hospital of Xinxiang Medical University, Weihui, Henan 453100, P.R. China
Published online on: March 24, 2015 https://doi.org/10.3892/mmr.2015.3539
Pages: 1258-1264

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

Viral myocarditis (VM), a severe clinical condition characterized by cardiac inflammation, is most frequently induced as a result of coxsackievirus infection. Evidence suggests that microRNAs may have significant roles in the progression of cardiac injury during coxsackievirus infection. Concurrently, microRNA (miR)‑214 was found to be upregulated in the plasma and myocardial cells during this process. In the present study, eight candidate miRNAs, the functions of which are associated with myocarditis, were selected and their expression levels were evaluated by reverse transcription-quantitative polymerase chain reaction. miR‑146b and miR‑214 were found to have significantly upregulated expression levels in the heart tissues of patients with VM compared with those of the control subjects. Predictions via the use of online bioinformatics tools and confirmed by dual‑luciferase assay and western blot analysis, revealed that ITCH, an NF‑κB signaling suppressor, was a target gene of miR‑214. To investigate the biological function of miR‑214, tumor necrosis factor‑α and interleukin‑6 expression levels were evaluated in HeLa cell culture supernatant. The results revealed that miR‑214 overexpression enhanced the expression of the two cytokines. In addition, the function of miR‑214 was partially rescued by ITCH overexpression. Subsequently, concurrent results were obtained following experiments in murine cardiac myocytes. In conclusion, the results of the present study demonstrated that miR‑214 contributed to the adverse inflammatory response to viral infection of the heart during coxsackievirus infection and is therefore a potential therapeutic target for the treatment of viral myocarditis.

View Figures

View References

1	Duncan BW, Bohn DJ, Atz AM, French JW, Laussen PC and Wessel DL: Mechanical circulatory support for the treatment of children with acute fulminant myocarditis. J Thorac Cardiovasc Surg. 122:440–448. 2001. View Article : Google Scholar : PubMed/NCBI
2	Woodruff JF: Viral myocarditis. A review. Am J Pathol. 101:425–484. 1980.PubMed/NCBI
3	Bowles NE, Richardson PJ, Olsen EG and Archard LC: Detection of Coxsackie-B-virus-specific RNA sequences in myocardial biopsy samples from patients with myocarditis and dilated cardiomyopathy. Lancet. 1:1120–1123. 1986. View Article : Google Scholar : PubMed/NCBI
4	Kandolf R, Klingel K, Mertsching H, et al: Molecular studies on enteroviral heart disease: patterns of acute and persistent infections. Eur Heart J. 12(Suppl D): 49–55. 1991. View Article : Google Scholar : PubMed/NCBI
5	Morimoto S, Hiramitsu S, Yamada K, et al: Clinical and pathologic features of chronic myocarditis: four autopsy cases presenting as dilated cardiomyopathy in life. Am J Cardiovasc Pathol. 4:181–191. 1992.PubMed/NCBI
6	Maier R, Krebs P and Ludewig B: Immunopathological basis of virus-induced myocarditis. Clin Dev Immunol. 11:1–5. 2004. View Article : Google Scholar : PubMed/NCBI
7	Shauer A, Gotsman I, Keren A, et al: Acute viral myocarditis: current concepts in diagnosis and treatment. Isr Med Assoc J. 15:180–185. 2013.PubMed/NCBI
8	Bartel DP: MicroRNAs: Genomics, biogenesis, mechanism, and function. Cell. 116:281–297. 2004. View Article : Google Scholar : PubMed/NCBI
9	De Rosa S, Curcio A and Indolfi C: Emerging role of microRNAs in cardiovascular diseases. Circ J. 78:567–575. 2014. View Article : Google Scholar : PubMed/NCBI
10	Corsten MF, Papageorgiou A, Verhesen W, et al: MicroRNA profiling identifies microRNA-155 as an adverse mediator of cardiac injury and dysfunction during acute viral myocarditis. Circ Res. 111:415–425. 2012. View Article : Google Scholar : PubMed/NCBI
11	Maes OC, Chertkow HM, Wang E and Schipper HM: MicroRNA: implications for alzheimer disease and other human CNS disorders. Curr Genomics. 10:154–168. 2009. View Article : Google Scholar : PubMed/NCBI
12	Xu J, Li Y, Wang F, et al: Suppressed miR-424 expression via upregulation of target gene Chk1 contributes to the progression of cervical cancer. Oncogene. 32:976–987. 2013. View Article : Google Scholar
13	Farazi TA, Hoell JI, Morozov P and Tuschl T: MicroRNAs in human cancer. Adv Exp Med Biol. 774:1–20. 2013.PubMed/NCBI
14	Corsten MF, Dennert R, Jochems S, et al: Circulating MicroRNA-208b and MicroRNA-499 reflect myocardial damage in cardiovascular disease. Circ Cardiovasc Genet. 3:499–506. 2010. View Article : Google Scholar : PubMed/NCBI
15	Shen Y, Xu W, Chu YW, Wang Y, Liu QS and Xiong SD: Coxsackievirus group B type 3 infection upregulates expression of monocyte chemoattractant protein 1 in cardiac myocytes, which leads to enhanced migration of mononuclear cells in viral myocarditis. J Virol. 78:12548–12556. 2004. View Article : Google Scholar : PubMed/NCBI
16	Liu YL, Wu W, Xue Y, et al: MicroRNA-21 and -146b are involved in the pathogenesis of murine viral myocarditis by regulating TH-17 differentiation. Arch Virol. 158:1953–1963. 2013. View Article : Google Scholar : PubMed/NCBI
17	Tijsen AJ, Pinto YM and Creemers EE: Circulating microRNAs as diagnostic biomarkers for cardiovascular diseases. Am J Physiol Heart Circ Physiol. 303:H1085–H1095. 2012. View Article : Google Scholar : PubMed/NCBI
18	Lewis BP, Burge CB and Bartel DP: Conserved seed pairing, often flanked by adenosines, indicates that thousands of human genes are microRNA targets. Cell. 120:15–20. 2005. View Article : Google Scholar : PubMed/NCBI
19	Thompson JD, Gibson TJ, Plewniak F, Jeanmougin F and Higgins DG: The CLUSTAL_X windows interface: Flexible strategies for multiple sequence alignment aided by quality analysis tools. Nucleic Acids Res. 25:4876–4882. 1997. View Article : Google Scholar
20	Esfandiarei M and McManus BM: Molecular biology and pathogenesis of viral myocarditis. Annu Rev Pathol. 3:127–155. 2008. View Article : Google Scholar
21	Klingel K and Kandolf R: The role of enterovirus replication in the development of acute and chronic heart muscle disease in different immunocompetent mouse strains. Scand J Infect Dis Suppl. 88:79–85. 1993.PubMed/NCBI
22	Fuse K, Chan G, Liu Y, et al: Myeloid differentiation factor-88 plays a crucial role in the pathogenesis of Coxsackievirus B3-induced myocarditis and influences type I interferon production. Circulation. 112:2276–2285. 2005. View Article : Google Scholar : PubMed/NCBI
23	Leipner C, Grün K, Borchers M and Stelzner A: The outcome of coxsackievirus B3-(CVB3-) induced myocarditis is influenced by the cellular immune status. Herz. 25:245–248. 2000. View Article : Google Scholar : PubMed/NCBI
24	Calabrese F and Thiene G: Myocarditis and inflammatory cardiomyopathy: microbiological and molecular biological aspects. Cardiovasc Res. 60:11–25. 2003. View Article : Google Scholar : PubMed/NCBI
25	Matsumori A, Yamada T, Suzuki H, Matoba Y and Sasayama S: Increased circulating cytokines in patients with myocarditis and cardiomyopathy. Br Heart J. 72:561–566. 1994. View Article : Google Scholar : PubMed/NCBI
26	Levine B, Kalman J, Mayer L, Fillit HM and Packer M: Elevated circulating levels of tumor necrosis factor in severe chronic heart failure. N Engl J Med. 323:236–241. 1990. View Article : Google Scholar : PubMed/NCBI
27	Schultz JC, Hilliard AA, Cooper LT Jr and Rihal CS: Diagnosis and treatment of viral myocarditis. Mayo Clin Proc. 84:1001–1009. 2009. View Article : Google Scholar : PubMed/NCBI
28	Xu HF, Ding YJ, Shen YW, et al: MicroRNA-1 represses Cx43 expression in viral myocarditis. Mol Cell Biochem. 362:141–148. 2012. View Article : Google Scholar
29	Hemida MG, Ye X, Zhang HM, et al: MicroRNA-203 enhances coxsackievirus B3 replication through targeting zinc finger protein-148. Cell Mol Life Sci. 70:277–291. 2013. View Article : Google Scholar