Peroxisome Proliferator–Activated Receptor-γ Activation Prevents Sepsis-Related Cardiac Dysfunction and Mortality In Mice
- 1 May 2013
- journal article
- research article
- Published by Ovid Technologies (Wolters Kluwer Health) in Circulation: Heart Failure
- Vol. 6 (3), 550-562
- https://doi.org/10.1161/circheartfailure.112.000177
Abstract
Background—: Cardiac dysfunction with sepsis is associated with both inflammation and reduced fatty acid oxidation. We hypothesized that energy deprivation accounts for sepsis-related cardiac dysfunction. Methods and Results—: Escherichia coli lipopolysaccharide (LPS) administered to C57BL/6 mice (wild type) induced cardiac dysfunction and reduced fatty acid oxidation and mRNA levels of peroxisome proliferator–activated receptor (PPAR)-α and its downstream targets within 6–8 hours. Transgenic mice in which cardiomyocyte-specific expression of PPARγ is driven by the α-myosin heavy chain promoter (αMHC-PPARγ) were protected from LPS-induced cardiac dysfunction. Despite a reduction in PPARα, fatty acid oxidation and associated genes were not decreased in hearts of LPS-treated αMHC-PPARγ mice. LPS treatment, however, continued to induce inflammation-related genes, such as interleukin-1α, interleukin-1β, interleukin-6, and tumor necrosis factor-α in hearts of αMHC-PPARγ mice. Treatment of wild-type mice with LPS and the PPARγ agonist, rosiglitazone, but not the PPARα agonist (WY-14643), increased fatty acid oxidation, prevented LPS-mediated reduction of mitochondria, and treated cardiac dysfunction, as well as it improved survival, despite continued increases in the expression of cardiac inflammatory markers. Conclusions—: Activation of PPARγ in LPS-treated mice prevented cardiac dysfunction and mortality, despite development of cardiac inflammation and PPARα downregulation.Keywords
This publication has 51 references indexed in Scilit:
- Inhibition of c-Jun-N-terminal Kinase Increases Cardiac Peroxisome Proliferator-activated Receptor α Expression and Fatty Acid Oxidation and Prevents Lipopolysaccharide-induced Heart DysfunctionJournal of Biological Chemistry, 2011
- PGC-1β Deficiency Accelerates the Transition to Heart Failure in Pressure Overload HypertrophyCirculation Research, 2011
- Toll-Like Receptor-Mediated Inflammatory Signaling Reprograms Cardiac Energy Metabolism by Repressing Peroxisome Proliferator-Activated Receptor γ Coactivator-1 SignalingCirculation: Heart Failure, 2011
- Cardiomyocyte lipids impair β-adrenergic receptor function via PKC activationAmerican Journal of Physiology-Endocrinology and Metabolism, 2011
- Preferential Oxidation of Triacylglyceride-Derived Fatty Acids in Heart Is Augmented by the Nuclear Receptor PPARαCirculation Research, 2010
- Cardiomyocyte Toll-like receptor 4 is involved in heart dysfunction following septic shock or myocardial ischemiaJournal of Molecular and Cellular Cardiology, 2010
- Molecular mechanism underlying the suppression of lipid oxidation during endotoxemiaMolecular Immunology, 2009
- Animal models of sepsis and sepsis-induced kidney injuryJCI Insight, 2009
- LPS-induced autophagy is mediated by oxidative signaling in cardiomyocytes and is associated with cytoprotectionAmerican Journal of Physiology-Heart and Circulatory Physiology, 2009
- Angiopoietin-like protein 4 converts lipoprotein lipase to inactive monomers and modulates lipase activity in adipose tissueProceedings of the National Academy of Sciences of the United States of America, 2006