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.


RESULTS
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-1α (PGC1α) and genes required for mitochondrial oxidative phosphorylation, which precede the onset of cardiac dysfunction. TWEAK-induced downregulation of PGC1α requires expression of its cell surface receptor, fibroblast growth factor-inducible 14 (Fn14). We further find that TWEAK downregulates PGC1α gene expression via the TNF receptor-associated factor 2 (TRAF2) and NFκB signaling pathways. Maintaining PGC1α levels through adenoviral-mediated gene expression is sufficient to protect against TWEAK-induced cardiomyocyte dysfunction.


CONCLUSIONS
Collectively, our data suggest that TWEAK induces cardiac dysfunction via downregulation of PGC1α, through FN14-TRAF2-NFκB-dependent signaling. Selective targeting of the FN14-TRAF2-NFκB-dependent signaling pathway or augmenting PGC1α levels may serve as novel therapeutic strategies for cardiomyopathy and heart failure.
Cardiac Muscle Research Laboratory, Cardiovascular Division, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, United States of America.
Jianru
J
Shi
Bingbing
B
Jiang
Yiling
Y
Qiu
Jian
J
Guan
Mohit
M
Jain
Xin
X
Cao
Michael
M
Bauer
Lihe
L
Su
Linda C
LC
Burkly
Teresa C
TC
Leone
Daniel P
DP
Kelly
Ronglih
R
Liao
D000818:Animals; D015153:Blotting, Western; D002478:Cells, Cultured; D000074049:Cytokine TWEAK; D004452:Echocardiography; D005346:Fibroblast Growth Factors / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D032383:Myocytes, Cardiac / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D051381:Rats; D017208:Rats, Wistar; D020133:Reverse Transcriptase Polymerase Chain Reaction; D047992:TNF Receptor-Associated Factor 2 / Q000378:metabolism; D015534:Trans-Activators / Q000378:metabolism; D014157:Transcription Factors; D048069:Tumor Necrosis Factors / Q000235:genetics / Q000378:metabolism*
D000074049:Cytokine TWEAK; D016328:NF-kappa B; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; C485290:Ppargc1a protein, mouse; D047992:TNF Receptor-Associated Factor 2; C109743:TNFSF12 protein, human; D015534:Trans-Activators; D014157:Transcription Factors; D048069:Tumor Necrosis Factors; C112971:fibroblast growth factor 14; D005346:Fibroblast Growth Factors