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.
Heart Rhythm Center, Division of Cardiology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan.
J Mol Cell Cardiol. 2018 Sep;122:69-79. doi: 10.1016/j.yjmcc.2018.08.005. Epub 2018 Aug 8.
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.
The level of inflammation and Th17 cell (CD4IL-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.
The expression of IL-17 and its downstream target genes may play fundamental roles in inducing VA in ischemic HF.
我们旨在研究白细胞介素（IL）-17 对缺血性心力衰竭（HF）模型中心室重构和室性心律失常（VA）发生的影响。在心肌缺血期间，促炎细胞因子 IL-17 的表达上调，并在梗死后炎症中起重要作用。然而，IL-17 对 VA 发生的影响尚未得到研究。
通过流式细胞术、定量聚合酶链反应（qPCR）和酶联免疫吸附测定（ELISA）研究了兔缺血性 HF 模型中的炎症水平和 Th17 细胞（CD4IL-17）表达。使用电生理技术和光学映射确定了急性和慢性给予 IL-17 后 IL-17 对 VA 诱导的影响。使用 qPCR、ELISA 和免疫印迹法测量了体内和体外的 IL-17 靶基因及其相关细胞因子和趋化因子的表达。在缺血性 HF 兔模型中，Th17 细胞明显增加。IL-17 以剂量依赖性方式直接在体内和体外诱导 VA。IL-17 降低了传导速度，延长了动作电位持续时间，并增加了左心室（LV）复极曲线的斜率。IL-17 处理导致 LV 纤维化、胶原生成和细胞凋亡。此外，增加的 IL-17 信号激活丝裂原活化蛋白激酶并增加下游靶基因 IL-6、TNF、CCL20 和 CXCL1 的表达。抗 IL-17 中和抗体消除了 IL-17 的作用。
IL-17 及其下游靶基因的表达可能在缺血性 HF 中诱导 VA 中起基本作用。
