Interleukin-17 enhances cardiac ventricular remodeling via activating MAPK pathway in ischemic heart failure

Shih Lin Chang*, Ya Wen Hsiao, Yung Nan Tsai, Shien-Fong Lin, Shuen Hsin Liu, Yenn Jiang Lin, Li Wei Lo, Fa Po Chung, Tze Fan Chao, Yu Feng Hu, Ta Chuan Tuan, Jo Nan Liao, Yu Cheng Hsieh, Tsu Juey Wu, Satoshi Higa, Shih Ann Chen

*Corresponding author for this work

Research output: Contribution to journalArticle

11 Scopus citations

Abstract

Background: We aimed to investigate the impact of interleukin (IL)-17 on ventricular remodeling and the genesis of ventricular arrhythmia (VA) in an ischemic heart failure (HF) model. The expression of the proinflammatory cytokine IL-17 is upregulated during myocardial ischemia and plays a fundamental role in post-infarct inflammation. However, the influence of IL-17 on the genesis of VA has not yet been studied. Methods and results: The level of inflammation and Th17 cell (CD4+IL-17+) expression in the rabbit model of ischemic HF were studied by flow cytometry, quantitative polymerase chain reaction (qPCR), and enzyme-linked immunosorbent assay (ELISA). The effect of IL-17 on VA induction following acute and chronic administration of IL-17 was determined using electrophysiological techniques and optical mapping. The expression of IL-17 target genes and related cytokines and chemokines in vivo and in vitro were measured using qPCR, ELISA, and immunoblotting. Th17 cells were markedly increased in the ischemic HF rabbit model. IL-17 directly induced VA in vivo and in vitro in a dose-dependent manner. IL-17 decreased conduction velocity, lengthened action potential duration, and increased the slope of the left ventricle (LV) restitution curve. IL-17 treatment led to fibrosis, collagen production and apoptosis in the LV. Furthermore, increased IL-17 signaling activated mitogen-activated protein kinase and increased the expression of downstream target genes, IL-6, TNF, CCL20, and CXCL1. An anti-IL-17 neutralizing antibody abolished the effects of IL-17. Conclusions: The expression of IL-17 and its downstream target genes may play fundamental roles in inducing VA in ischemic HF.

Original languageEnglish
Pages (from-to)69-79
Number of pages11
JournalJournal of Molecular and Cellular Cardiology
Volume122
DOIs
StatePublished - 1 Sep 2018

Keywords

  • IL-17
  • Inflammation
  • MAPK
  • Ventricular arrhythmias

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    Chang, S. L., Hsiao, Y. W., Tsai, Y. N., Lin, S-F., Liu, S. H., Lin, Y. J., Lo, L. W., Chung, F. P., Chao, T. F., Hu, Y. F., Tuan, T. C., Liao, J. N., Hsieh, Y. C., Wu, T. J., Higa, S., & Chen, S. A. (2018). Interleukin-17 enhances cardiac ventricular remodeling via activating MAPK pathway in ischemic heart failure. Journal of Molecular and Cellular Cardiology, 122, 69-79. https://doi.org/10.1016/j.yjmcc.2018.08.005