Abstract 19005: PGC1α Play a Critical Role in TWEAK Mediating Cardiac Dysfunction

Inflammatory cytokines contribute to the pathogenesis of cardiac dysfunction and symptomatic heart failure (HF). We recently identified that a novel TNF superfamily member, tumor necrosis factor-like weak inducer of apoptosis (TWEAK), was increased in patients with HF. Genetic overexpression of TWEAK in mice results in dilated cardiomyopathy and HF. This study was performed to investigate the molecular mechanisms underlying TWEAK-induced cardiomyocyte dysfunction. Methods and Results. Circulating levels of TWEAK were increased in mice through IV injection of recombinant TWEAK (r-TWEAK). r-TWEAK resulted in cardiac dysfunction and deleterious remodeling in a dose dependent manner. Histologic examination of r-TWEAK hearts revealed severe mitochondrial damage. In conjunction with mitochondrial pathology, genes required for mitochondrial oxidative phosphorylation were downregulated with r-TWEAK treatment. Importantly, PGC1α, a key regulator of mitochondrial gene transcription was downregulated in r-TWEAK hearts prior to the onset of cardiac dysfunction, suggesting a potential causal relationship. In isolated adult rat cardiomyocytes, r-TWEAK recapitulated contractile dysfunction, suggesting a cell autonomous mechanism. Adenoviral-mediated overexpression of PGC1α maintained mitochondrial levels in r-TWEAK-treated cardiomyocytes and protected against r-TWEAK induced contractile dysfunction, as revealed by percent cell fraction shortening experiments (control 4.23±0.22%; r-TWEAK 2.73±0.31%, p<0.05 vs. control; PGC1α+r-TWEAK 4.23±0.25%, p<0.05 vs. r-TWEAK). Using shRNA mediated genetic silencing and adenoviral-mediated overexpression, we further implicate the upstream signaling molecule TRAF2, and the downstream regulator NFκB in TWEAK regulation of PGC1α, mitochondrial levels, and cardiomyocyte dysfunction. Conclusion. Our data identify TRAF2-NFκB-PCG1 axis as a critical molecular mechanism to the development of TWEAK-induced cardiomyocyte dysfunction and the development of HF. Modulation of mitochondrial levels or antagonism of TRAF2-NFκB may serve as candidate therapeutic targets for the treatment of heart failure.