The role of purine nucleotide metabolism in cardiac decompensation and failure

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Project Summary Currently, 6.5 million Americans are diagnosed with heart failure, a cardiovascular disease that is classically defined as the impaired ability of the heart to pump oxygenated and nutrient full blood to meet the demands of the body. The mechanical function of the heart is driven by the chemical free energy provided by ATP hydrolysis. Physiological rates of myocardial ATP consumption require the heart to resynthesize its entire ATP pool several times per minute. In the failing heart, cardiomyocyte metabolic dysfunction leads to a reduction in the chemical potential that is available to drive cellular processes. The concentrations of creatine (Cr), phosphocreatine (CrP), and ATP and the CrP/ATP ratio are diminished in heart failure, while levels of inorganic phosphate are increased. These changes in energy metabolite levels have been shown to be driven, at least in part, by reductions in total adenine nucleotide (TAN) pool levels. In vivo the TAN pools are maintained via a balance between the purine de novo synthesis and degradation pathways. In disease there is an increase in mammalian target of rapamycin complex 1 (mTORC1) phosphorylation, which causes an upregulation of the purine de novo synthesis pathway. In addition, it has been observed that levels of enzymes involved in the purine degradation pathway are decreased during failure. Furthermore, reductions in TAN should kinetically activate the purine synthesis pathway. Together, these compensations are not enough to maintain physiological TAN pool levels in heart failure. The goals of this proposal are to elucidate the underlying mechanism driving the depletion of the TAN pools in heart failure and to explore possible therapeutics to reverse this pathological metabolite depletion in patients with heart failure. The hypothesis of this study is that in a high demand state associated with the pressure- and volume-overloaded heart, the metabolic state of the myocardium is shifted towards purine degradation. This shift is only partially compensated for by changes in expression level of enzymes in the synthesis and degradation pathways. In three aims, we will assay and modulate expression of key genes in the purine degradation, salvation, and de novo synthesis pathways that are differentially regulated in heart failure, to test our hypothesis, and to identify and test novel molecular targets to reverse myocardial energetic dysfunction.