PPAR{alpha} augments heart function and cardiac fatty acid oxidation in early experimental polymicrobial sepsis

Children with sepsis and multisystem organ failure have downregulated leukocyte gene expression of peroxisome proliferator-activated receptor-α (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 h 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 h after initiation of sepsis by echocardiography, was higher in WT mice than in Ppara–/– mice. Ex vivo working heart studies demonstrated greater developed pressure, contractility, and aortic outflow in WT compared with 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 unlikel...

Source: AJP: Heart and Circulatory Physiology - January 31, 2017 Category: Cardiology Authors: Standage, S. W., Bennion, B. G., Knowles, T. O., Ledee, D. R., Portman, M. A., McGuire, J. K., Liles, W. C., Olson, A. K. Tags: Energetics and Metabolism RESEARCH ARTICLE Source Type: research