Shih-Lin Chang1, Ya-Wen Hsiao2, Yung-Nan Tsai3, Shien-Fong Lin4, Shuen-Hsin Liu5, Yenn-Jiang Lin3, Li-Wei Lo3, Fa-Po Chung3, Tze-Fan Chao3, Yu-Feng Hu3, Ta-Chuan Tuan3, Jo-Nan Liao3, Yu-Cheng Hsieh6, Tsu-Juey Wu6, Satoshi Higa7, Shih-Ann Chen3. 1. Heart Rhythm Center, Division of Cardiology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan; Institute of Clinical Medicine, Department of Medicine, School of Medicine, National Yang-Ming University, Taipei, Taiwan. Electronic address: ep.slchang@msa.hinet.net. 2. Heart Rhythm Center, Division of Cardiology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan. 3. Heart Rhythm Center, Division of Cardiology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan; Institute of Clinical Medicine, Department of Medicine, School of Medicine, National Yang-Ming University, Taipei, Taiwan. 4. Institute of Biomedical Engineering, National Chiao Tung University, Hsinchu, Taiwan. 5. Shuang-Ho Hospital, Taipei Medical University, Taipei, Taiwan. 6. Institute of Clinical Medicine, Department of Medicine, School of Medicine, National Yang-Ming University, Taipei, Taiwan; Division of Cardiology, Department of Medicine, Taichung Veterans General Hospital, Taichung, Taiwan. 7. Cardiac Electrophysiology and Pacing Laboratory, Division of Cardiovascular Medicine, Makiminato Central Hospital, Okinawa, Japan.
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.
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.