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Toll-like receptor-mediated inflammatory signaling reprograms cardiac energy metabolism by repressing peroxisome proliferator-activated receptor γ coactivator-1 signaling.
- Source :
-
Circulation. Heart failure [Circ Heart Fail] 2011 Jul; Vol. 4 (4), pp. 474-82. Date of Electronic Publication: 2011 May 10. - Publication Year :
- 2011
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Abstract
- Background: Currently, there are no specific therapies available to treat cardiac dysfunction caused by sepsis and other chronic inflammatory conditions. Activation of toll-like receptor 4 (TLR4) by lipopolysaccharide (LPS) is an early event in Gram-negative bacterial sepsis, triggering a robust inflammatory response and changes in metabolism. Peroxisome proliferator-activated receptor-γ coactivator-1 (PGC-1) α and β serve as critical physiological regulators of energy metabolic gene expression in heart.<br />Methods and Results: Injection of mice with LPS triggered a myocardial fuel switch similar to that of the failing heart: reduced mitochondrial substrate flux and myocyte lipid accumulation. The LPS-induced metabolic changes were associated with diminished ventricular function and suppression of the genes encoding PGC-1α and β, known transcriptional regulators of mitochondrial function. This cascade of events required TLR4 and nuclear factor-κB activation. Restoration of PGC-1β expression in cardiac myocytes in culture and in vivo in mice reversed the gene regulatory, metabolic, and functional derangements triggered by LPS. Interestingly, the effects of PGC-1β overexpression were independent of the upstream inflammatory response, highlighting the potential utility of modulating downstream metabolic derangements in cardiac myocytes as a novel strategy to prevent or treat sepsis-induced heart failure.<br />Conclusions: LPS triggers cardiac energy metabolic reprogramming through suppression of PGC-1 coactivators in the cardiac myocyte. Reactivation of PGC-1β expression can reverse the metabolic and functional derangements caused by LPS-TLR4 activation, identifying the PGC-1 axis as a candidate therapeutic target for sepsis-induced heart failure.
- Subjects :
- Animals
Cells, Cultured
Disease Models, Animal
Fatty Acids metabolism
Heart Failure chemically induced
Heart Failure physiopathology
Lipid Metabolism drug effects
Lipid Metabolism physiology
Lipopolysaccharides adverse effects
Lipopolysaccharides pharmacology
Male
Mice
Mice, Inbred C57BL
Mice, Knockout
Myocardium pathology
Myocytes, Cardiac drug effects
Myocytes, Cardiac metabolism
Myocytes, Cardiac pathology
NF-kappa B metabolism
Reactive Oxygen Species metabolism
Signal Transduction drug effects
Toll-Like Receptor 4 genetics
Transcription Factors metabolism
Energy Metabolism physiology
Heart Failure metabolism
Myocardium metabolism
Signal Transduction physiology
Toll-Like Receptor 4 metabolism
Transcription Factors antagonists & inhibitors
Subjects
Details
- Language :
- English
- ISSN :
- 1941-3297
- Volume :
- 4
- Issue :
- 4
- Database :
- MEDLINE
- Journal :
- Circulation. Heart failure
- Publication Type :
- Academic Journal
- Accession number :
- 21558447
- Full Text :
- https://doi.org/10.1161/CIRCHEARTFAILURE.110.959833