Cardiomyocytes disrupt pyrimidine biosynthesis in nonmyocytes to regulate heart repair
Shen Li, … , Caius G. Radu, Arjun Deb
Shen Li, … , Caius G. Radu, Arjun Deb
Published November 23, 2021
Citation Information: J Clin Invest. 2022;132(2):e149711. https://doi.org/10.1172/JCI149711.
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Research Article Cardiology

Cardiomyocytes disrupt pyrimidine biosynthesis in nonmyocytes to regulate heart repair

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.

Authors

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 J. Lusis, Thomas G. Graeber, Caius G. Radu, Arjun Deb

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Figure 3

Genetic deletion of ENPP1 leads to enhanced cardiac repair and better preservation of postinjury heart function.

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Genetic deletion of ENPP1 leads to enhanced cardiac repair and better pr...
(A) Western blotting for ENPP1 expression in the hearts of ENPP1CKO animals at 7 days following cardiac injury and (B) quantitative densitometry of ENPP1 expression (n = 4). (C) B mode and M mode echocardiogram demonstrating better contractile function with decreased chamber dilatation at 4 weeks following cardiac injury (green arrows, diastole; yellow arrows, systole). (D) EF and fractional shortening as well as LV chamber size (LVID) in systole and diastole over 4 weeks after cardiac injury in control and ENPP1CKO animals. (E) Pie chart demonstrating fraction of animals with mild, moderate, and severe reductions in EF. (F) Masson trichrome staining demonstrating scar size (blue) measured at the apex and midventricle and (G) quantitation of differences in scar size as a fraction of the LV surface area. (H) Pie chart showing animals (%) with mild, moderate, and severe fibrosis. (I) Heart weight (HW), body weight (BW), and HW/BW ratios measured at 4 weeks following cardiac injury and (J) cardiac troponin T immunostaining to determine myocyte surface area (arrowheads) at the border zone and quantitation of myocyte surface area. Scale bar: 10 μm. (K) Number of capillaries (CD31 staining, arrowheads) in ENPP1CKO and control animals at 4 weeks after heart injury and quantitation of capillary density. Scale bar: 10 μm. Data are represented as mean ± SEM. **P < 0.01; *P < 0.05, ordinary 1-way ANOVA with Tukey’s multiple comparison test (B), ordinary 2-way ANOVA with Šidák’s multiple comparisons test (D), or 2-tailed Student’s t test (G, I–K). n = 14 in control and n = 16 in ENPP1CKO animals (D, E, and G– K).