PGC1α Plays a Critical Role in TWEAK-Induced Cardiac Dysfunction

Background: Inflammatory cytokines play an important role in the pathogenesis of heart failure. We have recently found the cytokine TWEAK (tumor necrosis factor (TNF)-like weak inducer of apoptosis), a member of the TNF superfamily, to be increased in patients with cardiomyopathy and result in the development of heart failure when overexpressed in mice. The molecular mechanisms underlying TWEAK-induced cardiac pathology, however, remain unknown. Methodology and Critical Finding: Using mouse models of elevated circulating TWEAK levels, established through intravenous injection of adenovirus expressing TWEAK or recombinant TWEAK protein, we find that TWEAK induces a progressive dilated cardiomyopathy with impaired contractile function in mice. Moreover, TWEAK treatment is associated with decreased expression of peroxisome proliferator-activated receptor gamma coactivator-1 alpha (PGC1 alpha) and genes required for mitochondrial oxidative phosphorylation, which precede the onset of cardiac dysfunction. TWEAK-induced downregulation of PGC1 alpha requires expression of its cell surface receptor, fibroblast growth factor-inducible 14 (Fn14). We further find that TWEAK downregulates PGC1 alpha gene expression via the TNF receptor-associated factor 2 (TRAF2) and NFkB signaling pathways. Maintaining PGC1 alpha levels through adenoviral-mediated gene expression is sufficient to protect against TWEAK-induced cardiomyocyte dysfunction. Conclusion: Collectively, our data suggest that TWEAK induces cardiac dysfunction via downregulation of PGC1 alpha, through FN14-TRAF2-NF kappa B-dependent signaling. Selective targeting of the FN14-TRAF2-NF kappa B-dependent signaling pathway or augmenting PGC1 alpha levels may serve as novel therapeutic strategies for cardiomyopathy and heart failure.