Abstract
Various populations of cells are recruited to the heart after cardiac injury, but little is known about whether cardiomyocytes directly regulate heart repair. Using a murine model of ischemic cardiac injury, we demonstrate that cardiomyocytes play a pivotal role in heart repair by regulating nucleotide metabolism and fates of nonmyocytes. Cardiac injury induced the expression of the ectonucleotidase ectonucleotide pyrophosphatase/phosphodiesterase 1 (ENPP1), which hydrolyzes extracellular ATP to form AMP. In response to AMP, cardiomyocytes released adenine and specific ribonucleosides that disrupted pyrimidine biosynthesis at the orotidine monophosphate (OMP) synthesis step and induced genotoxic stress and p53-mediated cell death of cycling nonmyocytes. As nonmyocytes are critical for heart repair, we showed that rescue of pyrimidine biosynthesis by administration of uridine or by genetic targeting of the ENPP1/AMP pathway enhanced repair after cardiac injury. We identified ENPP1 inhibitors using small molecule screening and showed that systemic administration of an ENPP1 inhibitor after heart injury rescued pyrimidine biosynthesis in nonmyocyte cells and augmented cardiac repair and postinfarct heart function. These observations demonstrate that the cardiac muscle cell regulates pyrimidine metabolism in nonmuscle cells by releasing adenine and specific nucleosides after heart injury and provide insight into how intercellular regulation of pyrimidine biosynthesis can be targeted and monitored for augmenting tissue repair.
Highlights
Myocardial infarction (MI) is a leading cause of systolic heart failure [1]
As cell death was related to cycling, we examined in detail the phases of cell cycle that were disrupted in nonmyocytes treated with ectonucleotide pyrophosphatase/phosphodiesterase 1 (ENPP1)+ATP myocyte conditioned medium (MCndM)
Our observations demonstrate what we believe is a hitherto unappreciated role of cardiomyocytes in regulating the cardiac repair response by modulating pyrimidine biosynthesis and fates of nonmuscle cells
Summary
Myocardial infarction (MI) is a leading cause of systolic heart failure [1]. After MI, different cell types are recruited to the heart in a spatiotemporally regulated manner to contribute to wound healing. We demonstrate that the cardiac muscle cell plays a pivotal role in regulating the cardiac repair response by releasing metabolites that disrupt cellular function of nonmyocyte cells, such as macrophages, fibroblasts, and endothelial and smooth muscle cells, and worsen wound healing. We demonstrate that genetic or pharmacologic targeting of the ENPP1/AMP cascade in the injured heart attenuates cardiomyocyte-induced defects of pyrimidine biosynthesis in nonmyocytes and leads to superior postinfarct cardiac function. Taken together, these observations shed insight into the role of the cardiac muscle cell in regulating nucleotide metabolism and cellular function of nonmyocytes and into how such myocyte-induced defects of pyrimidine biosynthesis in cycling nonmyocytes can be targeted to enhance repair and postinjury heart function
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