RESEARCH ARTICLE Energetics and Metabolism: PPARalpha augments heart function and cardiac fatty acid oxidation in early experimental polymicrobial sepsis

摘要

Standage SW, Bennion BG, Knowles TO, Ledee DR, Portman MA, McGuire JK, Liles WC, Olson AK. PPARa augments heart function and cardiac fatty acid oxidation in early experimental polymicrobial sepsis. Am J Physiol Heart Circ Physiol 312: H239-H249, 2017. First published November 23, 2016; doi:10.1152/ajpheart. 00457.2016.Children with sepsis and multisystem organ failure have downregulated leukocyte gene expression of peroxisome prolif-erator-activated receptor-a (PPARalpha), a nuclear hormone receptor transcription factor that regulates inflammation and lipid metabolism. Mouse models of sepsis have likewise demonstrated that the absence of PPARa 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 PPARalpha (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 unlikely at this stage of sepsis. These data suggest that PPARa expression supports the hyperdynamic cardiac response early in the course of sepsis and that increased fatty acid oxidation may prevent morbidity and mortality. NEW & NOTEWORTHY In contrast to previous studies in septic shock using experimental mouse models, we are the first to demonstrate that heart function increases early in sepsis with an associated augmentation of cardiac fatty acid oxidation. Absence of peroxisome proliferator-activated receptor-a (PPARa) results in reduced cardiac performance and fatty acid oxidation in sepsis.