Peroxisome Proliferator-Activated Receptor-γ Activation Prevents Sepsis-Related Cardiac Dysfunction and Mortality In Mice

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)-alpha and its downstream targets within 6-8 hours. Transgenic mice in which cardiomyocyte-specific expression of PPAR gamma is driven by the alpha-myosin heavy chain promoter (alpha MHC-PPAR gamma) were protected from LPS-induced cardiac dysfunction. Despite a reduction in PPAR alpha, fatty acid oxidation and associated genes were not decreased in hearts of LPS-treated alpha MHC-PPAR gamma mice. LPS treatment, however, continued to induce inflammation-related genes, such as interleukin-1 alpha, interleukin-1 beta, interleukin-6, and tumor necrosis factor-alpha in hearts of alpha MHC-PPAR gamma mice. Treatment of wild-type mice with LPS and the PPAR gamma agonist, rosiglitazone, but not the PPAR alpha 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 PPAR gamma in LPS-treated mice prevented cardiac dysfunction and mortality, despite development of cardiac inflammation and PPAR alpha downregulation.