Peroxisome proliferator–activated receptor-γ activation prevents sepsis-related cardiac dysfunction and mortality in mice

K Drosatos, RS Khan, CM Trent, H Jiang… - Circulation: Heart …, 2013 - Am Heart Assoc
K Drosatos, RS Khan, CM Trent, H Jiang, NH Son, WS Blaner, S Homma, PC Schulze
Circulation: Heart Failure, 2013Am Heart Assoc
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 …
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.
Am Heart Assoc