Abstract 17761: PPARα is Essential for Cardiac Metabolic Adaptation to Chronic Hypoxia
We postulated that PPARα plays a role in the metabolic changes caused by hypoxia in the heart, and used high fat feeding and gene deletion to alter PPARα activity. Control mice (129EvSv, n = 82) were exposed to 3 weeks of normobaric hypoxia at 11% oxygen, or to normoxia. Half the mice were fed a high (55%) fat diet, and half were chow fed (7.5% fat). In vivo cardiac function was measured using cine MRI. Hearts were isolated and perfused to measure fatty acid oxidation and glycolytic flux using 3H labeling. Hypoxia plus a high fat diet decreased cardiac output of control animals by 21% (p < 0.05), and ejection fraction by 12% (Fig 1, p < 0.05), and increased cardiac fatty acid oxidation by 30% (p < 0.01) compared with normoxic controls. Glycolytic flux was reduced by 38% (p < 0.01) in high fat fed mouse hearts irrespective of oxygen level. Cardiac function in control mice was unaffected by chronic hypoxia, with fatty acid oxidation reduced by 23% (p <0.05) and glycolytic flux increased 2-fold (p < 0.01). Mitochondrial uncoupling protein 3 (UCP3) levels, measured by Western blotting, were doubled (p < 0.01) in high fat fed hearts irrespective of oxygen level, but reduced by 27% in chow fed hypoxic hearts (p < 0.05). In PPARα−/− mouse hearts (n = 70), cardiac metabolism and UCP3 expression were unaltered by hypoxia and/or high fat feeding. In conclusion, PPARα activation, using high fat feeding, increased cardiac fatty acid oxidation and UCP3 expression, and decreased glycolytic flux, which decreased ejection fraction during hypoxia. Deletion of PPARα prevented metabolic adaptation to hypoxia, and consequently impaired cardiac function. Therefore PPARα plays pivotal metabolic, and thereby functional, roles in the hypoxic heart.
- © 2010 by American Heart Association, Inc.