Various population of cells are recruited to the heart after cardiac injury but little is known about whether the cardiomyocyte directly regulates heart repair. In a murine model of ischemic cardiac injury, we demonstrate that the cardiomyocyte plays a pivotal role in heart repair by regulating nucleotide metabolism and fates of non-myocytes. Cardiac injury induced the expression of the ectonucleotidase ENPP1 that hydrolyzes extracellular ATP to form AMP. In response to AMP, the cardiomyocyte released adenine and specific ribonucleosides that disrupted pyrimidine biosynthesis at OMP synthesis step, induced genotoxic stress and a p53 mediated cell death of cycling non-myocytes. As non-myocytes are critical for heart repair, we showed that rescue of pyrimidine biosynthesis by administration of uridine or by genetic targeting of ENPP1/AMP pathway enhanced repair after cardiac injury. We identified ENPP1 inhibitors on small molecule screening and showed that systemic administration of an ENPP1 inhibitor after heart injury rescued pyrimidine biosynthesis in non-myocyte cells, augmented cardiac repair and post infarct heart function. These observations demonstrate that the cardiac muscle cell by releasing adenine and specific nucleosides after heart injury regulates pyrimidine metabolism in non-muscle cells and provide insight into how inter-cellular regulation of pyrimidine biosynthesis can be targeted and monitored for augmenting tissue repair.
Shen Li, Tomohiro Yokota, Ping Wang, Johanna ten Hoeve, Feiyang Ma, Thuc M. Le, Evan R. Abt, Yonggang Zhou, Rimao Wu, Maxine Nanthavongdouangsy, Abraham Rodriguez, Yijie Wang, Yen-Ju Lin, Hayato Muranaka, Mark Sharpley, Demetrios T. Braddock, Vicky E. MacRae, Utpal Banerjee, Pei-Yu Chiou, Marcus Seldin, Dian Huang, Michael Teitell, Ilya Gertsman, Michael Jung, Steven J. Bensinger, Robert Damoiseaux, Kym Faull, Matteo Pellegrini, Aldons Lusis, Thomas G. Graeber, Caius G. Radu, Arjun Deb