Association between cytokines and two circulating micro-RNAs and development of premature ventricular contractions-induced cardiomyopathy

Document Type : Original Article

Authors

1 Physiology Department, School of Medicine, Iran University of Medical Sciences, Tehran, Iran

2 Cardiac Electrophysiology Research Center, Rajaie Cardiovascular Medical and Research Center, Iran University of Medical Sciences, Tehran, Iran

3 Physiology Research Center, Physiology Department, Faculty of Medicine, Iran University of Medical Sciences, Tehran, Iran

4 Blood Transfusion Research Center, High Institute for Research and Education in Transfusion Medicine, Tehran, Iran

Abstract

Objective(s): Recent progress in understanding the pathogenesis of premature ventricular contraction (PVC)-induced cardiomyopathy (PIC) has suggested a key role for inflammation. The aim of this study was to evaluate the expression of messenger RNAs (mRNAs) and the protein production of interleukin-6 (IL-6), IL-10, tumor necrosis factor alpha (TNF-α) and interferon-γ (IFN-γ) and two circulating micro-RNAs related to inflammation and cardiovascular disease; miR-155 and miR-146.
Materials and Methods: The study population was comprised 25 patients with PIC and 25 patients with normal left ventricular ejection fraction despite frequent PVCs. TNF-α, IL-6, IL10, and IFN-γ levels were evaluated in peripheral blood mononuclear cells (PBMCs) by flow cytometry and their mRNAs were assessed by real time PCR. We analyzed circulating levels of these cytokines by enzyme linked immunosorbent assay (ELISA). Two circulating micro-RNAs, miR-155 and miR-146a, were also investigated.
Results: The flow cytometry findings showed that the median fluorescence intensity (MFI) of antibodies reacted with the IL-6 and TNF-α were higher in PIC group than the control group (P-value<0.001). In ELISA, the levels of IL-6 (P-value <0.001) and TNF-α (P-value <0.001) and in RT-PCR the relative expression levels of IL-6 (P-value <0.001) and TNF-α (P-value <0.001) were significantly higher in the PIC group. The relative expression levels of miR-155 and miR-146a were not significantly different between 2 groups (P-value>0.05).
Conclusion: In our patients with PIC, there was an elevation in the expression levels of IL-6 and TNF-α in PBMCs. This finding may provide further insights into the inflammatory pathways involved in PIC.

Keywords

Main Subjects


1. Potfay J, Kaszala K, Tan AY, Sima AP, Gorcsan J, Ellenbogen KA, et al. Abnormal left ventricular mechanics of ventricular ectopic beats: Insights into origin and coupling interval in premature ventricular contraction-induced cardiomyopathy. Circ Arrhythm Electrophysiol 2015; 8:1194-1200.
2. Wang Y, Eltit JM, Kaszala K, Tan A, Jiang M, Zhang M, et al. Cellular mechanism of premature ventricular contraction-induced cardiomyopathy. Heart Rhythm 2014; 11:2064-2072.
3. Sadron Blaye-Felice M, Hamon D, Sacher F, Pascale P, Rollin A, Duparc A, et al.  Premature ventricular contraction-induced cardiomyopathy: Related clinical and electrophysiologic parameters. Heart Rhythm 2016; 13:103-110.
4. Olgun H, Yokokawa M, Baman T, Kim HM, Armstrong W, Good E, et al. The role of interpolation in PVC-induced cardiomyopathy. Heart Rhythm 2011; 8:1046-1049.
5. Gopinathannair R, Etheridge SP, Marchlinski FE, Spinale FG, Lakkireddy D, Olshansky B. Arrhythmia-induced cardiomyopathies: Mechanisms, recognition, and management. J Am Coll Cardiol 2015; 66:1714-1728.
6. Gomes JA, Bahia-Oliveira LM, Rocha MO, Martins-Filho OA, Gazzinelli G, Correa-Oliveira R. Evidence that development of severe cardiomyopathy in human chagas’ disease is due to a Th1-specific immune response. Infect Immun 2003; 71:1185-1193.
7. de Mello VD, Kolehmanien M, Schwab U, Pulkkinen L, Uusitupa M. Gene expression of peripheral blood mononuclear cells as a tool in dietary intervention studies: What do we know so far? Mol Nutr Food Res 2012; 56:1160-1172.
8. de Oliveira RT, Mamoni RL, Souza JR, Fernandes JL, Rios FJ, Gidlund M, et al. Differential expression of cytokines, chemokines and chemokine receptors in patients with coronary artery disease. Int J Cardiol 2009; 136:17-26.
9. Vadlamani L, Abraham WT. Insights into pathogenesis and treatment of cytokines in cardiomyopathy. Curr cardiol Rep 2000; 2:120-128.
10. Testa U, Pelosi E, Castelli G, Labbaye C. miR-146 and miR-155: Two key modulators of immune response and tumor development. Noncoding RNA 2017;3. pii: E22.
11. Pfeiffer D, Roßmanith E, Lang I, Falkenhagen D. miR-146a, miR-146b, and miR-155 increase expression of IL-6 and IL-8 and support HSP10 in an in vitro sepsis model. PLoS One 2017;12:e0179850.
12. Shanmugam N, Chua TP, Ward D. Frequent ventricular bigeminy-a reversible cause of dilated cardiomyopathy. How frequent is frequent? Eur J Heart Fail 2006; 6:869–873.
13. Penela D, Acosta J, Aguinaga L, Tercedor L, Ordoñez A, Fernández-Armenta J, et al. Ablation of frequent PVC in patients meeting criteria for primary prevention ICD implant: Safety of withholding the implant. Heart Rhythm 2015; 12:2434-2442.
14. Baser K, Bas HD, LaBounty T, Yokokawa M, Good E, Latchamsetty R, et al. Recurrence of PVCs in patients with PVC-induced cardiomyopathy. Heart Rhythm 2015; 12:1519-1523.
15. Cappuzzello C, Di Vito L, Melchionna R, Melillo G, Silvestri L, Cesareo E, et al. Ease of plasma IL-9 and decrease of plasma IL-5, IL-7, and IFN-γ in patients with chronic heart failure.  J Transl Med 2011; 9:28.
16. Varda-Bloom N, Leor J, Ohad DG, Hasin Y, Amar M, Fixler R, et al. Cytotoxic T lymphocytes are activated following myocardial infarction and can recognize and kill healthy myocytes in vitro. J Mol Cell Cardiol 2000; 32:2141–2149.
17. Harvey EJ, Ramji DP. Interferon-gamma and atherosclerosis: Pro-or anti-atherogenic? Cardiovas Res 2005; 67:11–20.
18. Hilfiker-Kleiner D, Landmesser U, Drexler H. Molecular mechanisms in heart failure: Focus on cardiac hypertrophy, inflammation, angiogenesis, and apoptosis. J Am Coll Cardiol 2006; 48: A56–66.
19. Sivasubramanian N, Coker ML, Kurrelmeyer KM, MacLellan WR, DeMayo FJ, Spinale FG, et al. Left ventricular remodeling in transgenic mice with cardiac restricted overexpression of tumor necrosis factor. Circulation 2001; 104:826–831.
20. Shirazi LF, Bissett J, Romeo F, Mehta JL. Role of Inflammation in Heart Failure. Curr Atheroscler Rep 2017;19:27.
21. Patten M, Kramer E, Bunemann J, Wenck C, Thoenes M, Wieland T, et al. Endotoxin and cytokines alter contractile protein expression in cardiac myocytes in vivo. Pflugers Arch 2001; 442:920–927.
22. Bronze-da-Rocha E. MicroRNAs expression profiles in cardiovascular diseases. Biomed Res Int 2014;2014: 985408.
23. Zhu J, Chen T, Yang L, Li Z, Wong MM, Zheng X, et al. Regulation of microRNA-155 in atherosclerotic inflammatory responses by targeting MAP3K10. PLoS One 2012;7:e46551.
24. Vickers KC, Rye KA, Tabet F. MicroRNAs in the onset and development of cardiovascular disease. Clin Sci (Lond)  2014; 126: 183-194.
25. Quan X, Ji Y, Zhang C, Guo X, Zhang Y, Jia S, et al. Circulating MiR-146a may be a potential biomarker of coronary heart disease in patients with subclinical hypothyroidism. Cell Physiol Biochem 2018;45:226-236.
26. Halkein J, Tabruyn SP, Ricke-Hoch M, Haghikia A, Nguyen NQ, Scherr M, et al. MicroRNA-146a is a therapeutic target and biomarker for peripartum cardiomyopathy. J Clin Invest 2013; 123:2143-154.
27. Kutty RK, Nagineni CN, Samuel W, Vijayasarathy C, Hooks JJ, Redmond TM. Inflammatory cytokines regulate microrna-155 expression in human retinal pigment epithelial cells by activating JAK/STAT pathway.  Biochem Biophys Res Commun 2010; 402:390-395.
28. Matsumoto S, Sakata Y, Nakatani D, Suna S, Mizuno H, Shimizu M, et al. A subset of circulating micrornas are predictive for cardiac death after
discharge for acute myocardial infarction. Biochem Biophys Res Commun 2012; 427:280-284.
29. Tian FJ, An LN, Wang GK, Zhu JQ, Li Q, Zhang YY, et al. Elevated microRNA-155 promotes foam cell formation by targeting HBP1 in atherogenesis.  Cardiovasc Res 2014; 103:100-110.
30. Ikitimur B, Cakmak HA, Coskunpinar E, Barman HA, Vural VA. The relationship between circulating microRNAs and left ventricular mass in symptomatic heart failure patients with systolic dysfunction. Kardiol Pol 2015; 73:740-746.
31. Sheedy FJ, O’Neill LA. Adding fuel to fire: MicroRNAs as a new class of mediators of inflammation. Ann Rheum Dis 2008; 67:iii50-55.