PMID- 23342071
OWN - NLM
STAT- MEDLINE
DCOM- 20130802
LR  - 20220309
IS  - 1932-6203 (Electronic)
IS  - 1932-6203 (Linking)
VI  - 8
IP  - 1
DP  - 2013
TI  - PGC1alpha plays a critical role in TWEAK-induced cardiac dysfunction.
PG  - e54054
LID - 10.1371/journal.pone.0054054 [doi]
LID - e54054
AB  - 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.
FAU - Shi, Jianru
AU  - Shi J
AD  - Cardiac Muscle Research Laboratory, Cardiovascular Division, Brigham and Women's 
      Hospital, Harvard Medical School, Boston, Massachusetts, United States of 
      America.
FAU - Jiang, Bingbing
AU  - Jiang B
FAU - Qiu, Yiling
AU  - Qiu Y
FAU - Guan, Jian
AU  - Guan J
FAU - Jain, Mohit
AU  - Jain M
FAU - Cao, Xin
AU  - Cao X
FAU - Bauer, Michael
AU  - Bauer M
FAU - Su, Lihe
AU  - Su L
FAU - Burkly, Linda C
AU  - Burkly LC
FAU - Leone, Teresa C
AU  - Leone TC
FAU - Kelly, Daniel P
AU  - Kelly DP
FAU - Liao, Ronglih
AU  - Liao R
LA  - eng
GR  - HL086967/HL/NHLBI NIH HHS/United States
GR  - R01 HL101189/HL/NHLBI NIH HHS/United States
GR  - R01 HL058493/HL/NHLBI NIH HHS/United States
GR  - HL099073/HL/NHLBI NIH HHS/United States
GR  - K08 HL107451/HL/NHLBI NIH HHS/United States
GR  - HL093147/HL/NHLBI NIH HHS/United States
GR  - R01 DK045416/DK/NIDDK NIH HHS/United States
GR  - R01 HL086967/HL/NHLBI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20130116
PL  - United States
TA  - PLoS One
JT  - PloS one
JID - 101285081
RN  - 0 (Cytokine TWEAK)
RN  - 0 (NF-kappa B)
RN  - 0 (Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha)
RN  - 0 (Ppargc1a protein, mouse)
RN  - 0 (TNF Receptor-Associated Factor 2)
RN  - 0 (TNFSF12 protein, human)
RN  - 0 (Trans-Activators)
RN  - 0 (Transcription Factors)
RN  - 0 (Tumor Necrosis Factors)
RN  - 0 (fibroblast growth factor 14)
RN  - 62031-54-3 (Fibroblast Growth Factors)
SB  - IM
MH  - Animals
MH  - Blotting, Western
MH  - Cells, Cultured
MH  - Cytokine TWEAK
MH  - Echocardiography
MH  - Fibroblast Growth Factors/metabolism
MH  - Male
MH  - Mice
MH  - Mice, Inbred C57BL
MH  - Myocytes, Cardiac/metabolism
MH  - NF-kappa B/metabolism
MH  - Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha
MH  - Rats
MH  - Rats, Wistar
MH  - Reverse Transcriptase Polymerase Chain Reaction
MH  - TNF Receptor-Associated Factor 2/metabolism
MH  - Trans-Activators/metabolism
MH  - Transcription Factors
MH  - Tumor Necrosis Factors/genetics/*metabolism
PMC - PMC3546975
COIS- Competing Interests: J.S., B.J., Y.Q., J.G., M.J., X.C., M.B., D.P.K. and R.L. 
      have declared no competing interests for this work. L.S. and L.C.B. are employees 
      of Biogen-IDEC, and the authors confirm that this does not alter the authors' 
      adherence to all the PLOS ONE policies on sharing data and materials.
EDAT- 2013/01/24 06:00
MHDA- 2013/08/03 06:00
PMCR- 2013/01/16
CRDT- 2013/01/24 06:00
PHST- 2012/11/05 00:00 [received]
PHST- 2012/12/05 00:00 [accepted]
PHST- 2013/01/24 06:00 [entrez]
PHST- 2013/01/24 06:00 [pubmed]
PHST- 2013/08/03 06:00 [medline]
PHST- 2013/01/16 00:00 [pmc-release]
AID - PONE-D-12-34556 [pii]
AID - 10.1371/journal.pone.0054054 [doi]
PST - ppublish
SO  - PLoS One. 2013;8(1):e54054. doi: 10.1371/journal.pone.0054054. Epub 2013 Jan 16.