Hostname: page-component-586b7cd67f-g8jcs Total loading time: 0 Render date: 2024-11-24T14:05:52.824Z Has data issue: false hasContentIssue false

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

Published online by Cambridge University Press:  17 June 2021

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]

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.

Type
Original Article
Copyright
© The Author(s), 2021. Published by Cambridge University Press

Access options

Get access to the full version of this content by using one of the access options below. (Log in options will check for institutional or personal access. Content may require purchase if you do not have access.)

References

Apitz, C, Webb, GD, Redington, AN. Tetralogy of Fallot. Lancet (London, England) 2009; 374: 14621471.CrossRefGoogle ScholarPubMed
Chai, PJ, Jacobs, JP, Quintessenza, JA. Modern surgical management of patients with tetralogy of Fallot. Cardiol Young 2013; 23: 905909.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: 549574.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: 837847.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: 391398.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): S272S278.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: 441447.Google ScholarPubMed
Barrett, T, Wilhite, SE, Ledoux, P, et al. NCBI GEO: archive for functional genomics data sets--update. Nucl Acids Res 2013; 41: D991S995.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: 1554515550.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: 267273.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: 17391740.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: 211219.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: 24982504.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: 840850.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: 20412057.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: 13351348.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: 4190341913.CrossRefGoogle ScholarPubMed
Hata, AN, Breyer, RM. Pharmacology and signaling of prostaglandin receptors: multiple roles in inflammation and immune modulation. Pharmacol Ther 2004; 103: 147166.CrossRefGoogle ScholarPubMed
Samuelsson, B. Role of basic science in the development of new medicines: examples from the eicosanoid field. J Biol Chem 2012; 287: 1007010080.CrossRefGoogle ScholarPubMed
Smyth, EM, Grosser, T, Wang, M, Yu, Y, FitzGerald, GA. Prostanoids in health and disease. Journal of lipid research. 2009; 50 (Suppl): S423S428.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: 15281534.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: 683693.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: 642649.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: 362372.CrossRefGoogle ScholarPubMed
Rudd, CE. T-cell signaling and immunopathologies. Semin Immunopathol 2010; 32: 9194.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: 1976219767.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: 954960.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: 466473.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: 414.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: 428434.Google Scholar
Landis, RC, Haskard, DO, Taylor, KM. New antiinflammatory and platelet-preserving effects of aprotinin. Ann Thorac Surg 2001; 72: S1808S1813.CrossRefGoogle ScholarPubMed
Mikawa, K, Akamatsu, H, Nishina, K, et al. Propofol inhibits human neutrophil functions. Anesth Analg 1998; 87: 695700.CrossRefGoogle ScholarPubMed
Supplementary material: File

Liu et al. supplementary material

Liu et al. supplementary material 1

Download Liu et al. supplementary material(File)
File 173.6 KB
Supplementary material: File

Liu et al. supplementary material

Liu et al. supplementary material 2

Download Liu et al. supplementary material(File)
File 81.9 KB
Supplementary material: File

Liu et al. supplementary material

Liu et al. supplementary material 3

Download Liu et al. supplementary material(File)
File 234 KB