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.