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Myocardial energetics and redox in health and disease
004 Peroxisome proliferator-activated receptor alpha is essential for cardiac adaptation to chronic hypoxia
  1. M Cole
  1. Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford, UK

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Deletion of the peroxisome proliferator-activated receptor alpha (PPARα) gene in mice results in abnormal cardiac substrate metabolism and PPARα−/− hearts have impaired function at high workload and increased post-ischaemic infarct size. We hypothesised that PPARα−/− mouse hearts would be intolerant to chronic hypoxia, and that PPARα is an essential regulator of metabolism in hypoxia. PPARα−/− mice (n=18) and wild-type (wt) controls (n=20) were exposed to 3 weeks of normobaric hypoxia. Control activated receptor alpha−/− (n=17) and wt mice (n=21) were housed in normoxic conditions within the same room. Oxygen content was reduced incrementally in the first week of housing, followed by 2 weeks at 11% oxygen. In-vivo cardiac function was measured using multislice cardiac magnetic resonance imaging. Hearts were perfused in the Langendorff mode to measure palmitate oxidation and glycolysis using 3H-labelled substrates. Cardiac output was unchanged in hypoxic wt and normoxic PPARα−/− mice, but was reduced by 31% by hypoxia in PPARα−/− mice (p<0.02). Late-stage ventricular filling was 46% lower in hypoxic PPARα−/− mice (p<0.01). Hypoxia reduced palmitate oxidation by 27% in mouse wt hearts, but did not affect PPARα−/− hearts. Hypoxia increased net lactate efflux 2.4-fold in hearts from wt animals (p<0.01), but lactate efflux from PPARα−/− hearts was unchanged with hypoxia. Hypoxia increased basal glycolytic flux 2.4-fold in wt hearts but did not alter lycolytic flux in PPARα−/− mouse hearts (p<0.01), which was already 3.7-fold greater than wt hearts. Thus PPARα−/− hearts lack the metabolic flexibility essential for adaptation to chronic hypoxia, and their inability to upregulate glycolysis probably impairs cardiac function.

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