Document Detail


Toll-like receptor-mediated inflammatory signaling reprograms cardiac energy metabolism by repressing peroxisome proliferator-activated receptor γ coactivator-1 signaling.
MedLine Citation:
PMID:  21558447     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
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.
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.
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.
Authors:
Joel Schilling; Ling Lai; Nandakumar Sambandam; Courtney E Dey; Teresa C Leone; Daniel P Kelly
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural     Date:  2011-05-10
Journal Detail:
Title:  Circulation. Heart failure     Volume:  4     ISSN:  1941-3297     ISO Abbreviation:  Circ Heart Fail     Publication Date:  2011 Jul 
Date Detail:
Created Date:  2011-07-20     Completed Date:  2011-09-15     Revised Date:  2013-06-30    
Medline Journal Info:
Nlm Unique ID:  101479941     Medline TA:  Circ Heart Fail     Country:  United States    
Other Details:
Languages:  eng     Pagination:  474-82     Citation Subset:  IM    
Affiliation:
Center for Cardiovascular Research, Department of Medicine, Washington University School of Medicine, St Louis, MO, USA.
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MeSH Terms
Descriptor/Qualifier:
Animals
Cells, Cultured
Disease Models, Animal
Energy Metabolism / physiology*
Fatty Acids / metabolism
Heart Failure / chemically induced,  metabolism*,  physiopathology
Lipid Metabolism / drug effects,  physiology
Lipopolysaccharides / adverse effects,  pharmacology
Male
Mice
Mice, Inbred C57BL
Mice, Knockout
Myocardium / metabolism*,  pathology
Myocytes, Cardiac / drug effects,  metabolism,  pathology
NF-kappa B / metabolism
Reactive Oxygen Species / metabolism
Signal Transduction / drug effects,  physiology*
Toll-Like Receptor 4 / genetics,  metabolism*
Transcription Factors / antagonists & inhibitors*,  metabolism
Grant Support
ID/Acronym/Agency:
DK052574/DK/NIDDK NIH HHS; HL058493/HL/NHLBI NIH HHS; HL077113/HL/NHLBI NIH HHS; K08 HL098373/HL/NHLBI NIH HHS; K08 HL098373/HL/NHLBI NIH HHS; K08 HL098373-03/HL/NHLBI NIH HHS; P30 DK052574-10/DK/NIDDK NIH HHS; P30 DK056341-08/DK/NIDDK NIH HHS; P30 DK56341/DK/NIDDK NIH HHS; P50 HL077113-05/HL/NHLBI NIH HHS; R01 HL058493-14/HL/NHLBI NIH HHS
Chemical
Reg. No./Substance:
0/Fatty Acids; 0/Lipopolysaccharides; 0/NF-kappa B; 0/Reactive Oxygen Species; 0/Tlr4 protein, mouse; 0/Toll-Like Receptor 4; 0/Transcription Factors; 0/peroxisome-proliferator-activated receptor-gamma coactivator-1
Comments/Corrections
Comment In:
Circ Heart Fail. 2011 Nov;4(6):e32; author reply e33   [PMID:  22086834 ]

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