MicroRNA‑34a mediates atrial fibrillation through regulation of Ankyrin‑B expression

Zhu,Yun; Feng,Zezhou; Cheng,Wei; Xiao,Yingbin

doi:10.3892/mmr.2018.8873

MicroRNA‑34a mediates atrial fibrillation through regulation of Ankyrin‑B expression

Authors:
- Yun Zhu
- Zezhou Feng
- Wei Cheng
- Yingbin Xiao
View Affiliations

Affiliations: Department of Cardiovascular Surgery, Xinqiao Hospital, Third Military Medical University, Chongqing 400037, P.R. China, Department of Thoracic and Cardiovascular Surgery, Southwest Hospital, Third Military Medical University, Chongqing 400037, P.R. China
Published online on: April 12, 2018 https://doi.org/10.3892/mmr.2018.8873
Pages: 8457-8465

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

Atrial fibrillation (AF) has a high prevalence and recurrence rate, and is associated with substantial mortality. However, its underlying mechanisms are not thoroughly understood. Increasing attention has been paid to the roles of microRNAs (miRs) in the pathogenesis of cardiovascular disease, including miR‑1 and miR‑133 (in the electrophysiological response), and miR‑34a (in cardiac fibrosis). Recently, Ankyrin‑B (Ank‑B), an adaptor protein, has been demonstrated to be associated with AF. As a predicted target gene of miR‑34a, the present study aimed to investigate if miR‑34a has a role in AF via regulation of Ank‑B expression. Western blot analysis revealed that the expression levels of Ank‑B was lower in the atrial tissue of AF patients than in individuals with sinus rate (SR); however, reverse transcription‑quantitative polymerase chain reaction data demonstrated that miR‑34a expression exhibited the opposite pattern. Dual‑luciferase assays following the specific overexpression or inhibition of miR‑34a indicated that the 3' untranslated region of Ankyrin 2 (the gene encoding Ank‑B) contained binding sites for miR‑34a. Furthermore, the expression levels of Ank‑B and sodium‑calcium exchanger 1 (an Ank‑B binding partner important in Ca2+ homeostasis), as well as intracellular Ca2+ signaling detected by Fluoro‑3 AM, were altered following the modulation of miR‑34a expression. Thus, miR‑34a may serve an important role in early electrophysiological remodeling and the development of AF via the regulation of Ank‑B expression. These results offer valuable insight into the underlying mechanism of AF, and provide a promising target for developing clinical diagnostic tools and potential therapies for patients with AF.

View Figures

View References

1	Heijman J, Guichard JB, Dobrev D and Nattel S: Translational challenges in atrial fibrillation. Circ Res. 122:752–773. 2018. View Article : Google Scholar : PubMed/NCBI
2	Miyasaka Y, Barnes ME, Gersh BJ, Cha SS, Bailey KR, Abhayaratna WP, Seward JB and Tsang TS: Secular trends in incidence of atrial fibrillation in Olmsted County, Minnesota, 1980 to 2000 and implications on the projections for future prevalence. Circulation. 114:119–125. 2006. View Article : Google Scholar : PubMed/NCBI
3	Dobrev D and Nattel S: New antiarrhythmic drugs for treatment of atrial fibrillation. Lancet. 375:1212–1223. 2010. View Article : Google Scholar : PubMed/NCBI
4	Iwasaki YK, Nishida K, Kato T and Nattel S: Atrial fibrillation pathophysiology: Implications for management. Circulation. 124:2264–2274. 2011. View Article : Google Scholar : PubMed/NCBI
5	Kashef F, Li J, Wright P, Snyder J, Suliman F, Kilic A, Higgins RS, Anderson ME, Binkley PF, Hund TJ and Mohler PJ: Ankyrin-B protein in heart failure: Identification of a new component of metazoan cardioprotection. J Biol Chem. 287:30268–30281. 2012. View Article : Google Scholar : PubMed/NCBI
6	Peter J, Mohler JQD and Bennett V: Ankyrin-B coordinates the Na/K ATPase, Na/Ca exchanger and insP3Receptor in a cardiac T-Tubule/SR microdomain. PLoS Biol. 3:e4232005. View Article : Google Scholar : PubMed/NCBI
7	Li J, Kline CF, Hund TJ, Anderson ME and Mohler PJ: Ankyrin-B regulates Kir6.2 membrane expression and function in heart. J Biol Chem. 285:28723–28730. 2010. View Article : Google Scholar : PubMed/NCBI
8	Schulze DH, Muqhal M, Lederer WJ and Ruknudin AM: Sodium/calcium exchanger (NCX1) macromolecular complex. J Biol Chem. 278:28849–28855. 2003. View Article : Google Scholar : PubMed/NCBI
9	Mohler TJ and Ha PJ: Ankyrin-based targeting pathway regulates human sinoatrial node automaticity. Channels (Austin). 2:404–406. 2008. View Article : Google Scholar : PubMed/NCBI
10	Small EM and Olson EN: Pervasive roles of microRNAs in cardiovascular biology. Nature. 469:336–342. 2011. View Article : Google Scholar : PubMed/NCBI
11	Care A, Catalucci D, Felicetti F, Bonci D, Addario A, Gallo P, Bang ML, Segnalini P, Gu Y, Dalton ND, et al: MicroRNA-133 controls cardiac hypertrophy. Nat Med. 13:613–618. 2007. View Article : Google Scholar : PubMed/NCBI
12	Boon RA, Iekushi K, Lechner S, Seeger T, Fischer A, Heydt S, Kaluza D, Tréguer K, Carmona G, Bonauer A, et al: MicroRNA-34a regulates cardiac ageing and function. Nature. 495:107–110. 2013. View Article : Google Scholar : PubMed/NCBI
13	Bernardo BC, Gao XM, Winbanks CE, Boey EJ, Tham YK, Kiriazis H, Gregorevic P, Obad S, Kauppinen S, Du XJ, et al: Therapeutic inhibition of the miR-34 family attenuates pathological cardiac remodeling and improves heart function. Proc Natl Acad Sci USA. 109:17615–17620. 2012. View Article : Google Scholar : PubMed/NCBI
14	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
15	Chen CL, Lin JL, Lai LP, Pan CH, Huang SK and Lin CS: Altered expression of FHL1, CARP, TSC-22 and P311 provide insights into complex transcriptional regulation in pacing-induced atrial fibrillation. Biochim Biophys Acta. 1772:317–329. 2007. View Article : Google Scholar : PubMed/NCBI
16	Mohler PJ, Splawski I, Napolitano C, Bottelli G, Sharpe L, Timothy K, Priori SG, Keating MT and Bennett V: A cardiac arrhythmia syndrome caused by loss of ankyrin-B function. Proc Natl Acad Sci USA. 101:9137–9142. 2004. View Article : Google Scholar : PubMed/NCBI
17	Terentyev D, Belevych AE, Terentyeva R, Martin MM, Malana GE, Kuhn DE, Abdellatif M, Feldman DS, Elton TS and Györke S: miR-1 overexpression enhances Ca(2+) release and promotes cardiac arrhythmogenesis by targeting PP2A regulatory subunit B56alpha and causing CaMKII-dependent hyperphosphorylation of RyR2. Circ Res. 104:514–521. 2009. View Article : Google Scholar : PubMed/NCBI
18	Tao H, Shi KH, Yang JJ, Huang C, Liu LP and Li J: Epigenetic regulation of cardiac fibrosis. Cell Signal. 25:1932–1938. 2013. View Article : Google Scholar : PubMed/NCBI
19	Song LS, Wang SQ, Xiao RP, Spurgeon H, Lakatta EG and Cheng H: Beta-adrenergic stimulation synchronizes intracellular Ca(2+) release during excitation-contraction coupling in cardiac myocytes. Circ Res. 88:794–801. 2001. View Article : Google Scholar : PubMed/NCBI
20	Pang H, Ronderos R, Pérez-Riera AR, Femenía F and Baranchuk A: Reverse atrial electrical remodeling A systematic review. Cardiol J. 18:625–631. 2011. View Article : Google Scholar : PubMed/NCBI
21	Verheule S, Tuyls E, Gharaviri A, Hulsmans S, van Hunnik A, Kuiper M, Serroyen J, Zeemering S, Kuijpers NH and Schotten U: Loss of continuity in the thin epicardial layer because of endomysial fibrosis increases the complexity of atrial fibrillatory conduction. Circ Arrhythm Electrophysiol. 6:202–211. 2013. View Article : Google Scholar : PubMed/NCBI
22	Le Scouarnec S, Bhasin N, Vieyres C, Hund TJ, Cunha SR, Koval O, Marionneau C, Chen B, Wu Y, Demolombe S, et al: Dysfunction in ankyrin-B-dependent ion channel and transporter targeting causes human sinus node disease. Proc Natl Acad Sci USA. 105:15617–15622. 2008. View Article : Google Scholar : PubMed/NCBI
23	Cunha SR, Hund TJ, Hashemi S, Voigt N, Li N, Wright P, Koval O, Li J, Gudmundsson H, Gumina RJ, et al: Defects in ankyrin-based membrane protein targeting pathways underlie atrial fibrillation. Circulation. 124:1212–1222. 2011. View Article : Google Scholar : PubMed/NCBI
24	Ono K, Kuwabara Y and Han J: MicroRNAs and cardiovascular diseases. FEBS J. 278:1619–1633. 2011. View Article : Google Scholar : PubMed/NCBI
25	Hund TJ, Wright PJ, Dun W, Snyder JS, Boyden PA and Mohler PJ: Regulation of the ankyrin-B-based targeting pathway following myocardial infarction. Cardiovasc Res. 81:742–749. 2009. View Article : Google Scholar : PubMed/NCBI