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Peroxisome proliferator-activated receptor-? activation prevents sepsis-related cardiac dysfunction and mortality in mice.

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

SUBMITTER: Drosatos K

PROVIDER: S-EPMC3690188 | biostudies-literature | 2013 May

REPOSITORIES: biostudies-literature

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

Drosatos Konstantinos K Khan Raffay S RS Trent Chad M CM Jiang Hongfeng H Son Ni-Huiping NH Blaner William S WS Homma Shunichi S Schulze P Christian PC Goldberg Ira J IJ

Circulation. Heart failure 20130409 3

<h4>Background</h4>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.<h4>Methods and results</h4>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. Tr ...[more]

PMID: 23572494

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Project description:Peroxisome proliferator-activated receptor-? is significantly down-regulated in circulating leukocytes from children with sepsis. Peroxisome proliferator-activated receptor-? null (Ppara) mice have greater mortality than wild-type mice when subjected to sepsis by cecal ligation and puncture. We sought to characterize the role of peroxisome proliferator-activated receptor-? in sepsis and to identify the mechanism whereby peroxisome proliferator-activated receptor-? confers a survival advantage.Prospective randomized preclinical study.Laboratory investigation.Male C57Bl/6J and Ppara mice (B6.129S4-Ppara/J), aged 12-16 weeks.Bone marrow chimeric mice were generated and subjected to cecal ligation and puncture. Survival was measured for 7 days. Separate groups of nontransplanted mice underwent cecal ligation and puncture and were euthanized 24 hours later for plasma and tissue analyses.Ppara mice had dramatically reduced survival compared with wild-type mice irrespective of the peroxisome proliferator-activated receptor-? status of the bone marrow they received (3% vs 63%; p < 0.0001). No difference in survival was observed between Ppara mice that received wild-type versus Ppara marrow or in wild-type mice receiving wild-type versus Ppara marrow. In septic, nontransplanted mice at 24 hours, Ppara mice had elevated cardiac troponin levels compared with wild-type mice. Cardiac histologic injury scores were greater in Ppara versus wild-type mice. Expression of transcription factors and enzymes related to fatty acid oxidation in the heart were profoundly down-regulated in both wild-type and Ppara mice, but more so in the Ppara mice.Peroxisome proliferator-activated receptor-? expression in nonhematopoietic tissues plays a critical role in determining clinical outcome in experimental polymicrobial sepsis and is more important to survival in sepsis than hematopoietic peroxisome proliferator-activated receptor-? expression. Cardiac injury due to inadequate energy production from fatty acid substrate is a probable mechanism of decreased survival in Ppara mice. These results suggest that altered peroxisome proliferator-activated receptor-?-mediated cellular metabolism may play an important role in sepsis-related end-organ injury and dysfunction, especially in the heart.

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Peroxisome proliferator-activated receptor-? activation prevents sepsis-related cardiac dysfunction and mortality in mice.

Publications

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

Similar Datasets

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