TWEAK/Fn14 axis is a positive regulator of cardiac hypertrophy

Abstract

Cardiac pressure overload-induced hypertrophy and pathological remodelling frequently leads to right ventricular dysfunction, which is the most frequent cause of death in patients with pulmonary arterial hypertension. Nowadays, accumulating reports support the concept that proinflammatory cytokines and growth factors play crucial roles in the failing heart. We recently identified Fn14 as an endogenous key regulator in cardiac fibrosis in the PAB (Pulmonary Artery Banding) pressure-overload model. Right ventricular overload after PAB is also characterized by hypertrophy. The aim of this study was to determine whether right ventricular (RV) cardiac hypertrophy induced by PAB is mediated by the TWEAK/Fn14 axis. After baseline MRI, Fn14−/− mice and wild-type (WT) littermates were randomly assigned to two groups: (1) SHAM-operated (n⩾4, per genotype) and (2) PAB (n⩾11, per genotype). The results of MRI and histological analysis demonstrated that Fn14−/− mice exhibit less PAB-induced cardiac hypertrophy compared to WT littermates. Moreover, Fn14 overexpression in cultured adult rat cardiomyocytes enhanced cardiomyocyte size. Collectively, our studies demonstrate that Fn14 ablation attenuates RV hypertrophy after PAB and that activation of TWEAK/Fn14 signaling promotes cardiomyocyte growth in vitro. These results nominate Fn14 as a potential novel target for the treatment of heart hypertrophy.