Adenine metabolism in cardiac repair

PROJECT SUMMARY/ABSTRACT The mammalian heart does not robustly regenerate after myocardial infarction and heals via a fibrotic repair response. Scar tissue is non-contractile, increases the hemodynamic burden on the remaining cardiac muscle and over time adverse cardiac remodeling occurs leading to ventricular dilatation and development of heart failure. Understanding mechanisms of ventricular remodeling to redirect the cardiac injury response from a fibrotic to a reparative one remains one of the broad therapeutic goals in cardiovascular medicine. We have recently identified extracellular nucleotide metabolism as a novel target for cardiac remodeling after ischemic cardiac injury. We demonstrated that after cardiac injury, the ectonucleotidase ENPP1 is upregulated and hydrolyzes extracellular ATP into AMP. Increased AMP was converted into adenine and extracellular adenine initiated a pro-inflammatory and pro-apoptotic cascade that caused cell death by disrupting NAD and pyrimidine biosynthesis in non-myocytes and myocytes. However the mechanisms of adenine generation and transport across the cell membrane, molecular and biochemical mechanisms of downstream effects on NAD and pyrimidine biosynthesis and whether the ENPP1/AMP/Adenine axis can be targeted for therapeutic gain to attenuate post infarct cardiac remodeling are unknown. In this proposal, we form a multi-disciplinary team comprising experts in cardiac physiology, metabolomics, computational biology, and finally population genetics to investigate the role of adenine metabolism in cardiac remodeling, identify its relevance as a potential therapeutic target and its association with human cardiomyopathy.