1. Nonhematopoietic Peroxisome Proliferator-Activated Receptor-α Protects Against Cardiac Injury and Enhances Survival in Experimental Polymicrobial Sepsis.
- Author
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Standage, Stephen W., Waworuntu, Rachel L., Delaney, Martha A., Maskal, Sara M., Bennion, Brock G., Duffield, Jeremy S., Parks, William C., Liles, W. Conrad, and McGuire, John K.
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PEROXISOME proliferator-activated receptors , *CARDIAC arrest , *SURVIVAL behavior (Humans) , *ANIMAL models in research , *HEALTH outcome assessment , *ANIMAL behavior , *ANIMAL experimentation , *BIOCHEMISTRY , *BIOLOGICAL models , *BLOOD sugar , *BODY weight , *BONE marrow transplantation , *GENE expression , *HEALTH status indicators , *LONGITUDINAL method , *PHENOMENOLOGY , *MICE , *MYOCARDIUM , *PROTEINS , *RESEARCH funding , *STATISTICAL sampling , *SEPSIS , *TROPONIN - Abstract
Objectives: Peroxisome proliferator-activated receptor-α is significantly down-regulated in circulating leukocytes from children with sepsis. Peroxisome proliferator-activated receptor-α 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-α in sepsis and to identify the mechanism whereby peroxisome proliferator-activated receptor-α confers a survival advantage.Design: Prospective randomized preclinical study.Setting: Laboratory investigation.Subjects: Male C57Bl/6J and Ppara mice (B6.129S4-Ppara/J), aged 12-16 weeks.Interventions: 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.Measurements and Main Results: Ppara mice had dramatically reduced survival compared with wild-type mice irrespective of the peroxisome proliferator-activated receptor-α 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.Conclusions: Peroxisome proliferator-activated receptor-α 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-α 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-α-mediated cellular metabolism may play an important role in sepsis-related end-organ injury and dysfunction, especially in the heart. [ABSTRACT FROM AUTHOR]- Published
- 2016
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