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Nonhematopoietic Peroxisome Proliferator-Activated Receptor-α Protects Against Cardiac Injury and Enhances Survival in Experimental Polymicrobial Sepsis.
- Source :
-
Critical Care Medicine . Aug2016, Vol. 44 Issue 8, pe594-e603. 19p. - Publication Year :
- 2016
-
Abstract
- <bold>Objectives: </bold>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.<bold>Design: </bold>Prospective randomized preclinical study.<bold>Setting: </bold>Laboratory investigation.<bold>Subjects: </bold>Male C57Bl/6J and Ppara mice (B6.129S4-Ppara/J), aged 12-16 weeks.<bold>Interventions: </bold>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.<bold>Measurements and Main Results: </bold>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.<bold>Conclusions: </bold>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]
- Subjects :
- *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
Subjects
Details
- Language :
- English
- ISSN :
- 00903493
- Volume :
- 44
- Issue :
- 8
- Database :
- Academic Search Index
- Journal :
- Critical Care Medicine
- Publication Type :
- Academic Journal
- Accession number :
- 116849840
- Full Text :
- https://doi.org/10.1097/CCM.0000000000001585