Abstract 229: TWEAK-Fn14 Axis: A Potential Therapeutic Target for Treating Heart Failure

Autor: Nehal J. Patel, Evelyn Thomas, Thomas J. Hund, Alexander J. Winkle, Sathyadev Unudurthi, Daniel Gratz
Rok vydání: 2019
Předmět:
Zdroj: Circulation Research. 125
ISSN: 1524-4571
0009-7330
DOI: 10.1161/res.125.suppl_1.229
Popis: Heart failure (HF) is a complex disease characterized by compromised cardiac structure and function. Previous work has identified a link between upregulation of pro-inflammatory cytokines, and HF. There is a critical need to gain better understanding of the inflammatory pathways in heart and identify novel therapeutic targets to regulate cardiac inflammation and HF Recent studies have shown that under stress macrophages are recruited to heart. These macrophages are mainly implicated in the release of inflammatory cytokines that promote cardiac fibrosis, eventually resulting in heart failure. Tumor necrosis factor (TNF)-like weak inducer of apoptosis (TWEAK) is a multifunctional member of the TNF superfamily, which binds to fibroblast growth factor inducible 14 (Fn14), a ubiquitously expressed cell-surface receptor. The TWEAK-Fn14 axis has been previously implicated in promoting inflammation in multiple autoimmune disorders, such as rheumatoid arthritis, however, its role in heart in not well known. The objective of this study is to test the hypothesis that TWEAK-Fn14 pathway promotes cardiac inflammation under stress, and blocking this pathway could be a potential therapeutic strategy to reduce stress induced cardiac inflammation and HF. Wild type (WT) and Fn14 knock out (Fn14 -/- ) mice were subjected to pressure overload induced stress (Trans aortic constriction or TAC) for 1 or 6 weeks. A subset of WT TAC animals were treated with the Fn14 inhibitor [L524-0366] (9mg/kg, IP daily) or vehicle beginning at day 3 following TAC. Macrophage infiltration and cardiac fibrosis were quantified in ventricular sections using F4/80 and Masson Trichrome staining respectively, and cardiac function was measured by echocardiography. Levels of monocyte chemoattractant protein-1 ( mcp-1 ) were measured by quantitative PCR. Genetic or chemical inhibition of Fn14 reduced fibrosis [40% lower compared to WT TAC] and improved cardiac function [Δ EF of 21.7%, n=6 for WT TAC; Δ EF of 14.2%, n=6 for Fn14 -/- TAC; Δ EF of 48.5%, n=3 for vehicle; Δ EF of 27.9%, n=5 for drug] compared to WT. Fn14 inhibition also reduced mcp-1 expression and macrophage infiltration [53.5% lower compared to WT TAC] .These results support TWEAK/Fn14 axis as a potential therapeutic target for treating HF
Databáze: OpenAIRE
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