Deletion of Fn14 receptor protects from right heart fibrosis and dysfunction

Abstract

Pulmonary arterial hypertension (PAH) is a fatal disease for which no cure is yet available. The leading cause of death in PAH is right ventricular (RV) failure. Previously, the TNF receptor superfamily member fibroblast growth factor-inducible molecule 14 (Fn14) has been associated with different fibrotic diseases. However, so far there is no study demonstrating a causal role for endogenous Fn14 signaling in RV or LV heart disease. The purpose of this study was to determine whether global ablation of Fn14 prevents RV fibrosis and remodeling improving heart function. Here, we provide evidence for a causative role of Fn14 in pulmonary artery banding (PAB)-induced RV fibrosis and dysfunction in mice. Fn14 expression was increased in the RV after PAB. Mice lacking Fn14 (Fn14−/−) displayed substantially reduced RV fibrosis and dysfunction following PAB compared to wild-type littermates. Cell culture experiments demonstrated that activation of Fn14 induces collagen expression via RhoA-dependent nuclear translocation of myocardin-related transcription factor-A (MRTF-A)/MAL. Furthermore, activation of Fn14 in vitro caused fibroblast proliferation and myofibroblast differentiation, which corresponds to suppression of PAB-induced RV fibrosis in Fn14−/− mice. Moreover, our findings suggest that Fn14 expression is regulated by endothelin-1 (ET-1) in cardiac fibroblasts. We conclude that Fn14 is an endogenous key regulator in cardiac fibrosis and suggest this receptor as potential new target for therapeutic interventions in heart failure.Electronic supplementary materialThe online version of this article (doi:10.1007/s00395-012-0325-x) contains supplementary material, which is available to authorized users.

The pathogenesis and treatment of cardiac atrophy in cancer cachexia

“…The inflammatory cytokine TWEAK and its receptor Fn14 negatively regulate skeletal muscle growth and function (104). However, recent in vivo studies using pharmacological and genetic modulation of TWEAK and Fn14 have also demonstrated a role for this pathway in the development of pathological cardiac hypertrophy, fibrosis, LV remodeling and dysfunction, and heart failure (31,51,81,85). We recently found that injection of H-Ras V12 oncogene transformed fibroblast cells with a lentiviral construct expressing the human Fn14 receptor into C57BL/6 mice, reduced heart mass, an effect that was prevented by treatment with an anti-Fn14 antibody (52).…”

Maintained right ventricular pressure overload induces ventricular–arterial decoupling in mice

“…Pulmonary artery banding (PAB) was performed as described previously by our group (Novoyatleva et al, 2013;Kojonazarov et al, 2013;Janssen et al, 2015).…”

Heightened TWEAK-NF-κB signaling and inflammation-associated fibrosis in paralyzed muscles of men with chronic spinal cord injury

“…Short-term TWEAK-TWEAK R activation promotes tissue repair and regeneration following an acute injury; however, during chronic injury or disease conditions, sustained TWEAK-TWEAK R activation may drive these responses toward a pathological remodeling in the muscle in which healthy tissue is replaced by fibrotic tissue (15,39,40). TWEAK-TWEAK R signaling promotes fibrogenic activities via increasing accumulation of fibroblasts (31,42) and/or increasing collagen gene expression (Col1a1 and Col1a2) (30,31) in skeletal muscle through its activation of inflammatory signaling pathways. For example, ablation of TWEAK R decreases fibrosis and expression of collagens in skeletal muscle of mice during aging (40).…”

“…TWEAK R, the smallest member of the TNF superfamily, has been identified as the unique TWEAK R (28,31,35). TWEAK R contains a TRAF binding site (9), which leads to downstream signaling and NF-B transcriptional regulation upon stimulation by TWEAK.…”