title: Peroxisome proliferator-activated receptor-γ activation prevents sepsis-related cardiac dysfunction and mortality in mice.
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.
  
  
  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.
authors.affiliation: Division of Preventive Medicine and Nutrition, Columbia University College of Physicians and Surgeons, New York, NY 10032, USA. kd2277@columbia.edu
authors.forename: Konstantinos
authors.initials: K
authors.lastname: Drosatos
authors.forename: Raffay S
authors.initials: RS
authors.lastname: Khan
authors.forename: Chad M
authors.initials: CM
authors.lastname: Trent
authors.forename: Hongfeng
authors.initials: H
authors.lastname: Jiang
authors.forename: Ni-Huiping
authors.initials: NH
authors.lastname: Son
authors.forename: William S
authors.initials: WS
authors.lastname: Blaner
authors.forename: Shunichi
authors.initials: S
authors.lastname: Homma
authors.forename: P Christian
authors.initials: PC
authors.lastname: Schulze
authors.forename: Ira J
authors.initials: IJ
authors.lastname: Goldberg
mesh_terms: D000818:Animals; D005227:Fatty Acids / Q000378:metabolism; D006331:Heart Diseases / Q000401:mortality / Q000503:physiopathology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009206:Myocardium / Q000378:metabolism; D047495:PPAR gamma / Q000819:agonists / Q000378:metabolism*; D000077154:Rosiglitazone; D018805:Sepsis / Q000150:complications* / Q000503:physiopathology / Q000628:therapy; D045162:Thiazolidinediones / Q000494:pharmacology; D018487:Ventricular Dysfunction, Left / Q000503:physiopathology
chemical_list: D005227:Fatty Acids; D047495:PPAR gamma; D045162:Thiazolidinediones; D000077154:Rosiglitazone
keywords: PPAR; cardiac metabolism; fatty acids; sepsis