| First Author | Shi J | Year | 2013 |
| Journal | PLoS One | Volume | 8 |
| Issue | 1 | Pages | e54054 |
| PubMed ID | 23342071 | Mgi Jnum | J:195698 |
| Mgi Id | MGI:5485082 | Doi | 10.1371/journal.pone.0054054 |
| Citation | Shi J, et al. (2013) PGC1alpha plays a critical role in TWEAK-induced cardiac dysfunction. PLoS One 8(1):e54054 |
| abstractText | 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-1alpha (PGC1alpha) and genes required for mitochondrial oxidative phosphorylation, which precede the onset of cardiac dysfunction. TWEAK-induced downregulation of PGC1alpha requires expression of its cell surface receptor, fibroblast growth factor-inducible 14 (Fn14). We further find that TWEAK downregulates PGC1alpha gene expression via the TNF receptor-associated factor 2 (TRAF2) and NFkappaB signaling pathways. Maintaining PGC1alpha 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 PGC1alpha, through FN14-TRAF2-NFkappaB-dependent signaling. Selective targeting of the FN14-TRAF2-NFkappaB-dependent signaling pathway or augmenting PGC1alpha levels may serve as novel therapeutic strategies for cardiomyopathy and heart failure. |
