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Toll-like receptor-mediated inflammatory signaling reprograms cardiac energy metabolism by repressing peroxisome proliferator-activated receptor γ coactivator-1 signaling.
Circ Heart Fail. 2011 Jul; 4(4):474-82.CH

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.

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+Show Affiliations

Center for Cardiovascular Research, Department of Medicine, Washington University School of Medicine, St Louis, MO, USA.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural

Language

eng

PubMed ID

21558447

Citation

Schilling, Joel, et al. "Toll-like Receptor-mediated Inflammatory Signaling Reprograms Cardiac Energy Metabolism By Repressing Peroxisome Proliferator-activated Receptor Γ Coactivator-1 Signaling." Circulation. Heart Failure, vol. 4, no. 4, 2011, pp. 474-82.
Schilling J, Lai L, Sambandam N, et al. Toll-like receptor-mediated inflammatory signaling reprograms cardiac energy metabolism by repressing peroxisome proliferator-activated receptor γ coactivator-1 signaling. Circ Heart Fail. 2011;4(4):474-82.
Schilling, J., Lai, L., Sambandam, N., Dey, C. E., Leone, T. C., & Kelly, D. P. (2011). Toll-like receptor-mediated inflammatory signaling reprograms cardiac energy metabolism by repressing peroxisome proliferator-activated receptor γ coactivator-1 signaling. Circulation. Heart Failure, 4(4), 474-82. https://doi.org/10.1161/CIRCHEARTFAILURE.110.959833
Schilling J, et al. Toll-like Receptor-mediated Inflammatory Signaling Reprograms Cardiac Energy Metabolism By Repressing Peroxisome Proliferator-activated Receptor Γ Coactivator-1 Signaling. Circ Heart Fail. 2011;4(4):474-82. PubMed PMID: 21558447.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Toll-like receptor-mediated inflammatory signaling reprograms cardiac energy metabolism by repressing peroxisome proliferator-activated receptor γ coactivator-1 signaling. AU - Schilling,Joel, AU - Lai,Ling, AU - Sambandam,Nandakumar, AU - Dey,Courtney E, AU - Leone,Teresa C, AU - Kelly,Daniel P, Y1 - 2011/05/10/ PY - 2011/5/12/entrez PY - 2011/5/12/pubmed PY - 2011/9/16/medline SP - 474 EP - 82 JF - Circulation. Heart failure JO - Circ Heart Fail VL - 4 IS - 4 N2 - 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. SN - 1941-3297 UR - https://www.unboundmedicine.com/medline/citation/21558447/Toll_like_receptor_mediated_inflammatory_signaling_reprograms_cardiac_energy_metabolism_by_repressing_peroxisome_proliferator_activated_receptor_γ_coactivator_1_signaling_ L2 - http://www.ahajournals.org/doi/full/10.1161/CIRCHEARTFAILURE.110.959833?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub=pubmed DB - PRIME DP - Unbound Medicine ER -