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Identification of IL-6 as a potential mediator of the myocardial fibrosis that occurs in response to surgery with cardiopulmonary bypass in children with Tetralogy of Fallot

Part of: Cardiac Morphology Tetralogy of Fallot (TOF) Basic Science Surgery

Published online by Cambridge University Press:  17 June 2021

Hongtao Liu Open the ORCID record for Hongtao Liu [Opens in a new window] ,
Yun Zhang ,
Zhenhai Wu  and
Liangqing Zhang
Hongtao Liu*
Affiliation:
Department of Anesthesiology, The First Affiliated Hospital of Jinan University, Guangzhou, Guangdong, China
Yun Zhang
Affiliation:
Basic Nursing Teaching and Research Section, Guangxi School of Traditional Chinese Medicine, Nanning, Guangxi, China
Zhenhai Wu
Affiliation:
Department of Anesthesiology, Liuzhou Hospital of Traditional Chinese Medicine, Liuzhou, Guangxi, China
Liangqing Zhang*
Affiliation:
Department of Anesthesiology, Affiliated Hospital of Guangdong Medical University, Zhanjiang, Guangdong, China
*
Author for correspondence: Hongtao Liu, MD, Department of Anesthesiology, The First Affiliated Hospital of Jinan University, 510632, Guangzhou, Guangdong, China. Tel: +8615977470206.E-mail: [email protected] and Liangqing Zhang, Prof., Department of Anesthesiology, Affiliated Hospital of Guangdong Medical University, Zhanjiang, Guangdong, China. Tel: 00860759-2387429; Fax: 00860759-2231754. E-mail: [email protected]
Author for correspondence: Hongtao Liu, MD, Department of Anesthesiology, The First Affiliated Hospital of Jinan University, 510632, Guangzhou, Guangdong, China. Tel: +8615977470206.E-mail: [email protected] and Liangqing Zhang, Prof., Department of Anesthesiology, Affiliated Hospital of Guangdong Medical University, Zhanjiang, Guangdong, China. Tel: 00860759-2387429; Fax: 00860759-2231754. E-mail: [email protected]
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Abstract

Background:

Tetralogy of Fallot is a common CHD. Studies have shown a close link between heart failure and myocardial fibrosis. Interleukin-6 has been suggested to be a post-independent factor of heart failure. This study aimed to explore the relationship between IL-6 and myocardial fibrosis during cardiopulmonary bypass.

Material and Methods:

We downloaded the expression profile dataset GSE132176 from Gene Expression Omnibus. After normalising the raw data, Gene Set Enrichment Analysis and differential gene expression analysis were performed using R. Further, a weighted gene correlation network analysis and a protein–protein interaction network analysis were used to identify HUB genes. Finally, we downloaded single-cell expression data for HUB genes using PanglaoDB.

Results:

There were 119 differentially expressed genes in right atrium tissues comparing the post-CPB group with the pre-CPB group. IL-6 was found to be significantly up-regulated in the post-CPB group. Six genes (JUN, FOS, ATF3, EGR1, IL-6, and PTGS2) were identified as HUB genes by a weighted gene correlation network analysis and a protein–protein interaction network analysis. Gene Set Enrichment Analysis showed that IL-6 affects the myocardium during CPB mainly through the JAK/STAT signalling pathway. Finally, we used PanglaoDB data to analyse the single-cell expression of the HUB genes.

Conclusion:

Our findings suggest that high expression of IL-6 and the activation of the JAK/STAT signalling pathway during CPB maybe the potential mechanism of myocardial fibrosis. We speculate that the high expression of IL-6 might be an important factor leading to heart failure after ToF surgery. We expect that these findings will provide a basis for the development of targeted drugs.

Keywords

Tetralogy of Fallotmyocardial fibrosiscardiopulmonary bypassIL-6WGCNAGSEA
Type
Original Article
Information
Cardiology in the Young , Volume 32 , Issue 2 , February 2022 , pp. 223 - 229
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Copyright
© The Author(s), 2021. Published by Cambridge University Press

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References

Apitz, C, Webb, GD, Redington, AN. Tetralogy of Fallot. Lancet (London, England) 2009; 374: 1462–1471.CrossRefGoogle ScholarPubMed
Chai, PJ, Jacobs, JP, Quintessenza, JA. Modern surgical management of patients with tetralogy of Fallot. Cardiol Young 2013; 23: 905–909.CrossRefGoogle ScholarPubMed
Yim, D, Riesenkampff, E, Caro-Dominguez, P, Yoo, SJ, Seed, M, Grosse-Wortmann, L. Assessment of diffuse ventricular myocardial fibrosis using native T1 in children with repaired tetralogy of Fallot. Circ Cardiovasc Imag 2017; 10.CrossRefGoogle Scholar
Kong, P, Christia, P, Frangogiannis, NG. The pathogenesis of cardiac fibrosis. Cell Mol Life Sci CMLS 2014; 71: 549–574.CrossRefGoogle ScholarPubMed
Dobaczewski, M, de Haan, JJ, Frangogiannis, NG. The extracellular matrix modulates fibroblast phenotype and function in the infarcted myocardium. J Cardiovasc Transl Res 2012; 5: 837–847.CrossRefGoogle ScholarPubMed
Tsutamoto, T, Hisanaga, T, Wada, A, et al. Interleukin-6 spillover in the peripheral circulation increases with the severity of heart failure, and the high plasma level of interleukin-6 is an important prognostic predictor in patients with congestive heart failure. J Am Coll Cardiol 1998; 31: 391–398.CrossRefGoogle ScholarPubMed
Bronicki, RA, Hall, M. Cardiopulmonary Bypass-Induced Inflammatory Response: pathophysiology and Treatment. Pediatr Crit Care Med J Soc Crit Care Med World Federation Pediatr Intens Crit Care Soc 2016; 17(Suppl 1): S272–S278.Google ScholarPubMed
Caputo, M, Mokhtari, A, Miceli, A, et al. Controlled reoxygenation during cardiopulmonary bypass decreases markers of organ damage, inflammation, and oxidative stress in single-ventricle patients undergoing pediatric heart surgery. J Thorac Cardiovasc Surg 2014; 148: 792–801.e8; discussion 0–1.CrossRefGoogle Scholar
Calza, G, Lerzo, F, Perfumo, F, et al. Clinical evaluation of oxidative stress and myocardial reperfusion injury in pediatric cardiac surgery. J Cardiovasc Surg 2002; 43: 441–447.Google ScholarPubMed
Barrett, T, Wilhite, SE, Ledoux, P, et al. NCBI GEO: archive for functional genomics data sets--update. Nucl Acids Res 2013; 41: D991–S995.CrossRefGoogle Scholar
Ritchie, ME, Phipson, B, Wu, D, et al. limma powers differential expression analyses for RNA-sequencing and microarray studies. Nucleic Acids Res 2015; 43: e47.CrossRefGoogle ScholarPubMed
Subramanian, A, Tamayo, P, Mootha, VK, et al. Gene set enrichment analysis: a knowledge-based approach for interpreting genome-wide expression profiles. Proc Nat Acad Sci 2005; 102: 15545–15550.CrossRefGoogle Scholar
Mootha, VK, Lindgren, CM, Eriksson, K-F, et al. PGC-1α-responsive genes involved in oxidative phosphorylation are coordinately downregulated in human diabetes. Nat Genet 2003; 34: 267–273.CrossRefGoogle ScholarPubMed
Liberzon, A, Subramanian, A, Pinchback, R, Thorvaldsdóttir, H, Tamayo, P, Mesirov, JP. Molecular signatures database (MSigDB) 3.0. Bioinf (Oxford, England) 2011; 27: 1739–1740.CrossRefGoogle ScholarPubMed
Langfelder, P, Horvath, S. WGCNA: an R package for weighted correlation network analysis. BMC Bioinf 2008; 9: 559.CrossRefGoogle Scholar
Nota, B. Gogadget: an R package for interpretation and visualization of GO enrichment results. Mol Inf 2017; 36.CrossRefGoogle Scholar
Lin, JS, Lai, EM. Protein-protein interactions: co-immunoprecipitation. Meth Mol Biol (Clifton, NJ) 2017; 1615: 211–219.CrossRefGoogle ScholarPubMed
Shannon, P, Markiel, A, Ozier, O, et al. Cytoscape: a software environment for integrated models of biomolecular interaction networks. Genome Res 2003; 13: 2498–2504.CrossRefGoogle ScholarPubMed
Chin, CH, Chen, SH, Wu, HH, Ho, CW, Ko, MT, Lin, CY. cytoHubba: identifying hub objects and sub-networks from complex interactome. BMC Syst Biol 2014; 8(Suppl 4): S11.CrossRefGoogle ScholarPubMed
Franzén, O, Gan, LM, Björkegren, JLM. PanglaoDB: a web server for exploration of mouse and human single-cell RNA sequencing data. Database J Biol Databases Curation 2019; 2019.CrossRefGoogle Scholar
Pan, Z, Sun, X, Shan, H, et al. MicroRNA-101 inhibited postinfarct cardiac fibrosis and improved left ventricular compliance via the FBJ osteosarcoma oncogene/transforming growth factor-β1 pathway. Circulation 2012; 126: 840–850.CrossRefGoogle ScholarPubMed
Li, Y, Li, Z, Zhang, C, et al. Cardiac fibroblast-specific activating transcription factor 3 protects against heart failure by suppressing MAP2K3-p38 signaling. Circulation 2017; 135: 2041–2057.CrossRefGoogle ScholarPubMed
Shen, J, Xing, W, Gong, F, et al. MiR-150–5p retards the progression of myocardial fibrosis by targeting EGR1. Cell Cycle 2019; 18: 1335–1348.CrossRefGoogle ScholarPubMed
Xiao, C, Wang, RH, Lahusen, TJ, et al. Progression of chronic liver inflammation and fibrosis driven by activation of c-JUN signaling in Sirt6 mutant mice. J Biol Chem 2012; 287: 41903–41913.CrossRefGoogle ScholarPubMed
Hata, AN, Breyer, RM. Pharmacology and signaling of prostaglandin receptors: multiple roles in inflammation and immune modulation. Pharmacol Ther 2004; 103: 147–166.CrossRefGoogle ScholarPubMed
Samuelsson, B. Role of basic science in the development of new medicines: examples from the eicosanoid field. J Biol Chem 2012; 287: 10070–10080.CrossRefGoogle ScholarPubMed
Smyth, EM, Grosser, T, Wang, M, Yu, Y, FitzGerald, GA. Prostanoids in health and disease. Journal of lipid research. 2009; 50 (Suppl): S423–S428.CrossRefGoogle ScholarPubMed
Ma, N, Szabolcs, MJ, Sun, J, et al. The effect of selective inhibition of cyclooxygenase (COX)-2 on acute cardiac allograft rejection. Transplantation 2002; 74: 1528–1534.CrossRefGoogle ScholarPubMed
Leslie, KO, Schwarz, J, Simpson, K, Huber, SA. Progressive interstitial collagen deposition in Coxsackievirus B3-induced murine myocarditis. Am J Pathol 1990; 136: 683–693.Google ScholarPubMed
Baumeister, D, Akhtar, R, Ciufolini, S, Pariante, CM, Mondelli, V. Childhood trauma and adulthood inflammation: a meta-analysis of peripheral C-reactive protein, interleukin-6 and tumour necrosis factor-α. Mol Psychiatry 2016; 21: 642–649.CrossRefGoogle ScholarPubMed
Chen, P, Long, B, Xu, Y, Wu, W, Zhang, S. Identification of crucial genes and pathways in human arrhythmogenic right ventricular cardiomyopathy by coexpression analysis. Front Physiol 2018; 9: 1778.CrossRefGoogle ScholarPubMed
Wang, J, Cheng, J, Zhang, C, Li, X. Cardioprotection effects of sevoflurane by regulating the pathway of neuroactive ligand-receptor interaction in patients undergoing coronary artery bypass graft surgery. Comput Math Meth Med 2017; 2017: 3618213.CrossRefGoogle ScholarPubMed
Wang, J, Chen, H, Cao, P, et al. Inflammatory cytokines induce caveolin-1/β-catenin signalling in rat nucleus pulposus cell apoptosis through the p38 MAPK pathway. Cell Proliferation 2016; 49: 362–372.CrossRefGoogle ScholarPubMed
Rudd, CE. T-cell signaling and immunopathologies. Semin Immunopathol 2010; 32: 91–94.CrossRefGoogle ScholarPubMed
Zelarayán, LC, Noack, C, Sekkali, B, et al. Beta-Catenin downregulation attenuates ischemic cardiac remodeling through enhanced resident precursor cell differentiation. Proc Nat Acad Sci USA 2008; 105: 19762–19767.CrossRefGoogle ScholarPubMed
Lemmens, K, Doggen, K, De Keulenaer, GW. Role of neuregulin-1/ErbB signaling in cardiovascular physiology and disease: implications for therapy of heart failure. Circulation 2007; 116: 954–960.CrossRefGoogle ScholarPubMed
Wang, L, Li, J, Li, D. Losartan reduces myocardial interstitial fibrosis in diabetic cardiomyopathy rats by inhibiting JAK/STAT signaling pathway. Int J Clin Exp Path 2015; 8: 466–473.Google ScholarPubMed
Biccard, BM, Goga, S, de Beurs, J. Dexmedetomidine and cardiac protection for non-cardiac surgery: a meta-analysis of randomised controlled trials. Anaesthesia 2008; 63: 4–14.CrossRefGoogle ScholarPubMed
Sato, Y, Ishikawa, S, Otaki, A, et al. Induction of acute-phase reactive substances during open-heart surgery and efficacy of ulinastatin. Inhibiting cytokines and postoperative organ injury. Japanese J Thoracic cardiovasc Surg Off Publ Japanese Assoc Thoracic Surg = Nihon Kyobu Geka Gakkai Zasshi 2000; 48: 428–434.Google Scholar
Landis, RC, Haskard, DO, Taylor, KM. New antiinflammatory and platelet-preserving effects of aprotinin. Ann Thorac Surg 2001; 72: S1808–S1813.CrossRefGoogle ScholarPubMed
Mikawa, K, Akamatsu, H, Nishina, K, et al. Propofol inhibits human neutrophil functions. Anesth Analg 1998; 87: 695–700.CrossRefGoogle ScholarPubMed
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