Hypoxia inducible factor-1 is a principal oxygen sensing molecule in all vertebrates. It is a transcription factor that is regulated by the effect of ambient oxygen concentration on its stability. HIF1 regulates a panoply of genes involved in response to hypoxia, including factors that augment angiogenesis and favor glycolytic metabolism. Nowhere are these responses of greater interest than in the heart, where hypoxia due to coronary artery disease is a major cause of morbidity and mortality in the developed world. We thus seek to determine the effects of HIF1 in the heart, to better understand the endogenous physiological response to hypoxia. We have created a transgenic model where HIF can be expressed in a regulated, cardiac-specific manner. We have generated our transgenic animal with a degradation-resistant HIF1 that is not affected by oxygen concentration. Our underlying hypothesis is that cardiac-specific elevation of HIF1 activity will direct the heart to recapitulate hypoxic responses.
Our specific aims test this hypothesis using a combination of molecular, metabolic and physiological techniques.
Specific Aim 1 : To identify the immediate down-stream targets of HIF1 transcriptional activation in vivo. We will apply comprehensive transcriptional analysis to our model as HIF1 activity increases to catch the first response and identify novel genes that are regulated by HIF1.
Specific Aim 2 : To measure the contribution of specific biochemical pathways to the HIF1-mediated switch from oxidative to glycolytic metabolism in the heart. This will be accomplished with the magnetic resonance spectroscopy of spin-labeled substrates.
Specific Aim 3 : To define the angiogenic effects of HIF1 overexpression in the heart. This will require histological and physiological analysis and will be explored in models of hypoxia and infarction.
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