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PGC1α plays a critical role in TWEAK-induced cardiac dysfunction
Jianru Shi1, Bingbing Jiang, Yiling Qiu
1Cardiac Muscle Research Laboratory, Cardiovascular Division, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, United States of America.
Plos One
|January 24, 2013
Summary
Tumor necrosis factor (TNF)-like weak inducer of apoptosis (TWEAK) causes heart failure by decreasing PGC1α levels. Restoring PGC1α protects against TWEAK-induced cardiac dysfunction, offering new therapeutic targets.
Area of Science:
- Cardiovascular Biology
- Molecular Medicine
- Cytokine Signaling
Background:
- Inflammatory cytokines are implicated in heart failure pathogenesis.
- Elevated tumor necrosis factor (TNF)-like weak inducer of apoptosis (TWEAK) is observed in cardiomyopathy patients and induces heart failure in mice.
- The precise molecular mechanisms of TWEAK-induced cardiac pathology are not fully understood.
Purpose of the Study:
- To elucidate the molecular mechanisms by which TWEAK leads to cardiac pathology.
- To investigate the role of peroxisome proliferator-activated receptor gamma coactivator-1α (PGC1α) in TWEAK-induced heart dysfunction.
- To identify potential therapeutic targets for TWEAK-mediated cardiomyopathy and heart failure.
Main Methods:
- Utilized mouse models with elevated circulating TWEAK levels (adenovirus-mediated expression or recombinant protein).
- Assessed cardiac function, contractile properties, and gene expression, focusing on PGC1α and mitochondrial oxidative phosphorylation.
- Investigated the involvement of fibroblast growth factor-inducible 14 (Fn14), TNF receptor-associated factor 2 (TRAF2), and NFκB signaling pathways.
Main Results:
- TWEAK overexpression induced progressive dilated cardiomyopathy and impaired contractile function in mice.
- TWEAK treatment decreased PGC1α expression and genes for mitochondrial oxidative phosphorylation prior to cardiac dysfunction.
- TWEAK-induced PGC1α downregulation was dependent on Fn14, TRAF2, and NFκB signaling.
- Augmenting PGC1α levels protected cardiomyocytes from TWEAK-induced dysfunction.
Conclusions:
- TWEAK induces cardiac dysfunction by downregulating PGC1α through the Fn14-TRAF2-NFκB signaling pathway.
- Targeting this pathway or increasing PGC1α levels represents a potential therapeutic strategy for heart failure.
- This study reveals a novel mechanism linking TWEAK signaling to mitochondrial dysfunction in the heart.
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