Permanent URL to this publication: http://dx.doi.org/10.5167/uzh-23358
Krishnan, J; Suter, M; Windak, R; Krebs, T; Felley, A; Montessuit, C; Tokarska-Schlattner, M; Aasum, E; Bogdanova, A; Perriard, E; Perriard, J C; Larsen, T; Pedrazzini, T; Krek, W (2009). Activation of a HIF1alpha-PPARgamma axis underlies the integration of glycolytic and lipid anabolic pathways in pathologic cardiac hypertrophy. Cell Metabolism, 9(6):512-524.
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Development of cardiac hypertrophy and progression to heart failure entails profound changes in myocardial metabolism, characterized by a switch from fatty acid utilization to glycolysis and lipid accumulation. We report that hypoxia-inducible factor (HIF)1alpha and PPARgamma, key mediators of glycolysis and lipid anabolism, respectively, are jointly upregulated in hypertrophic cardiomyopathy and cooperate to mediate key changes in cardiac metabolism. In response to pathologic stress, HIF1alpha activates glycolytic genes and PPARgamma, whose product, in turn, activates fatty acid uptake and glycerolipid biosynthesis genes. These changes result in increased glycolytic flux and glucose-to-lipid conversion via the glycerol-3-phosphate pathway, apoptosis, and contractile dysfunction. Ventricular deletion of Hif1alpha in mice prevents hypertrophy-induced PPARgamma activation, the consequent metabolic reprogramming, and contractile dysfunction. We propose a model in which activation of the HIF1alpha-PPARgamma axis by pathologic stress underlies key changes in cell metabolism that are characteristic of and contribute to common forms of heart disease.
|Item Type:||Journal Article, refereed, original work|
|Communities & Collections:||05 Vetsuisse Faculty > Institute of Veterinary Physiology|
|DDC:||570 Life sciences; biology|
|Deposited On:||21 Oct 2009 09:09|
|Last Modified:||27 Nov 2013 18:15|
|Citations:||Web of Science®. Times cited: 59|
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