# The role of purine nucleotide metabolism in cardiac decompensation and failure

> **NIH NIH F31** · UNIVERSITY OF MICHIGAN AT ANN ARBOR · 2022 · $39,369

## Abstract

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.

## Key facts

- **NIH application ID:** 10544141
- **Project number:** 5F31HL154605-02
- **Recipient organization:** UNIVERSITY OF MICHIGAN AT ANN ARBOR
- **Principal Investigator:** Rachel Lopez-Schenk
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $39,369
- **Award type:** 5
- **Project period:** 2021-07-01 → 2023-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10544141

## Citation

> US National Institutes of Health, RePORTER application 10544141, The role of purine nucleotide metabolism in cardiac decompensation and failure (5F31HL154605-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10544141. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*