The Frick Center for Heart Failure and Arrhythmia, Dorothy M. Davis Heart and Lung Research Institute, The Ohio State University Wexner Medical Center, Columbus, OH, USA; Department of Biomedical Engineering, College of Engineering, The Ohio State University, Columbus, OH, USA.
The Frick Center for Heart Failure and Arrhythmia, Dorothy M. Davis Heart and Lung Research Institute, The Ohio State University Wexner Medical Center, Columbus, OH, USA; Department of Biomedical Engineering, College of Engineering, The Ohio State University, Columbus, OH, USA.
Life Sci. 2020 Apr 15;247:117440. doi: 10.1016/j.lfs.2020.117440. Epub 2020 Feb 15.
Heart failure (HF) is characterized by compromised cardiac structure and function. Previous work has identified a link between upregulation of pro-inflammatory cytokines and HF. Tumor necrosis factor (TNF)-like weak inducer of apoptosis (TWEAK) is a pro-inflammatory cytokine, which binds to fibroblast growth factor inducible 14 (Fn14), a ubiquitously expressed cell-surface receptor. The objective of this study was to investigate the role of TWEAK/Fn14 pathway in promoting cardiac inflammation under non ischemic stress conditions.
Wild type (WT) and Fn14 knock out (Fn14) mice were subjected to pressure overload [transaortic constriction (TAC)] for 1 or 6 weeks. A subset of WT TAC animals were treated with the Fn14 antagonist L524-0366. Cardiac function was measured by echocardiography. Cardiac fibrosis and macrophage infiltration were quantified using immunohistochemistry and flow cytometry, respectively. Cardiac fibroblasts were isolated for quantifying TWEAK-induced chemokine release.
Fn14 mice displayed improved cardiac function, reduced fibrosis and lower macrophage infiltration in heart compared to WT following TAC. L524-0366 mitigated maladaptive remodeling with TAC. TWEAK induced secretion of the pro-inflammatory chemokine, monocyte chemoattractant protein 1 from WT but not Fn14 fibroblasts in vitro, in part through activation of non-canonical NF-κB signaling. Finally, Fn14 expression was increased in mouse following TAC and in human failing hearts.
Our findings support an important role for the TWEAK/Fn14 promoting macrophage infiltration and fibrosis in heart under non-ischemic stress, with potential for therapeutic intervention to improve cardiac function in the setting of HF.
心力衰竭（HF）的特征是心脏结构和功能受损。先前的工作已经确定了促炎细胞因子的上调与 HF 之间的联系。肿瘤坏死因子（TNF）样凋亡弱诱导物（TWEAK）是一种促炎细胞因子，它与成纤维细胞生长因子诱导 14（Fn14）结合，Fn14 是一种广泛表达的细胞表面受体。本研究的目的是研究 TWEAK/Fn14 途径在非缺血应激条件下促进心脏炎症的作用。
野生型（WT）和 Fn14 敲除（Fn14）小鼠接受主动脉缩窄（TAC）压力超负荷 1 或 6 周。WT TAC 动物的一部分接受 Fn14 拮抗剂 L524-0366 治疗。通过超声心动图测量心脏功能。通过免疫组织化学和流式细胞术分别量化心脏纤维化和巨噬细胞浸润。分离心脏成纤维细胞以定量 TWEAK 诱导的趋化因子释放。
与 WT 相比，Fn14 小鼠在 TAC 后心脏功能改善、纤维化减少和巨噬细胞浸润减少。L524-0366 减轻了 TAC 的适应性重构。TWEAK 在体外诱导 WT 但不诱导 Fn14 成纤维细胞分泌促炎趋化因子单核细胞趋化蛋白 1，部分通过非经典 NF-κB 信号通路的激活。最后，Fn14 在 TAC 后和人衰竭心脏中的表达增加。
我们的发现支持 TWEAK/Fn14 在非缺血应激下促进巨噬细胞浸润和纤维化在心脏中的重要作用，为 HF 患者改善心脏功能提供了治疗干预的潜力。
