Children with sepsis and multisystem organ failure have downregulated leukocyte gene expression of PPARα, a nuclear hormone receptor transcription factor that regulates inflammation and lipid metabolism. Mouse models of sepsis have likewise demonstrated that the absence of PPARα is associated with decreased survival and organ injury, specifically of the heart. Using a clinically relevant mouse model of early sepsis, we found that heart function increases in wild type (WT) mice over the first 24 hours of sepsis, but that mice lacking PPARα (Ppara-/-) cannot sustain the elevated heart function necessary to compensate for sepsis pathophysiology. Left ventricular shortening fraction, measured 24 hours after initiation of sepsis by echocardiography, was higher in WT mice than Ppara-/- mice. Ex vivo working heart studies demonstrated greater developed pressure, contractility, and aortic outflow in WT compared to Ppara-/- mice. Furthermore, cardiac fatty acid oxidation was increased in WT but not in Ppara-/- mice. Regulatory pathways controlling pyruvate incorporation into the citric acid cycle were inhibited by sepsis in both genotypes, but the regulatory state of enzymes controlling fatty acid oxidation appeared to be permissive in WT mice only. Mitochondrial ultrastructure was not altered in either genotype indicating that severe mitochondrial dysfunction is unlikely at this stage of sepsis. These data suggest that PPARα expression supports the hyperdynamic cardiac response early in the course of sepsis and that increased fatty acid oxidation may prevent morbidity and mortality.
- septic shock
- PPAR alpha
- cardiovascular failure
- fatty acid oxidation
- Copyright © 2016, American Journal of Physiology-Heart and Circulatory Physiology