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.

中文翻译：

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心肌细胞破坏非心肌细胞中嘧啶的生物合成以调节心脏修复

心脏损伤后，各种细胞群被募集到心脏，但对于心肌细胞是否直接调节心脏修复知之甚少。我们使用缺血性心脏损伤的小鼠模型，证明心肌细胞通过调节核苷酸代谢和非心肌细胞的命运在心脏修复中发挥关键作用。心脏损伤诱导外核苷酸酶外核苷酸焦磷酸酶/磷酸二酯酶 1 (ENPP1) 的表达，该酶水解细胞外 ATP 形成 AMP。作为对 AMP 的响应，心肌细胞释放腺嘌呤和特异性核糖核苷，这些核糖核苷在乳清酸单磷酸 (OMP) 合成步骤中破坏嘧啶生物合成，并诱导基因毒性应激和 p53 介导的循环非心肌细胞死亡。由于非心肌细胞对心脏修复至关重要，我们表明，通过施用尿苷或通过 ENPP1/AMP 通路的基因靶向来拯救嘧啶生物合成可增强心脏损伤后的修复。我们使用小分子筛选鉴定了 ENPP1 抑制剂，并表明在心脏损伤后全身给予 ENPP1 抑制剂可以挽救非心肌细胞中的嘧啶生物合成，并增强心脏修复和梗塞后心脏功能。这些观察结果表明，心肌细胞在心脏损伤后通过释放腺嘌呤和特定核苷来调节非肌肉细胞中的嘧啶代谢，并深入了解如何靶向和监测嘧啶生物合成的细胞间调节以促进组织修复。我们使用小分子筛选鉴定了 ENPP1 抑制剂，并表明在心脏损伤后全身给予 ENPP1 抑制剂可以挽救非心肌细胞中的嘧啶生物合成，并增强心脏修复和梗塞后心脏功能。这些观察结果表明，心肌细胞在心脏损伤后通过释放腺嘌呤和特定核苷来调节非肌肉细胞中的嘧啶代谢，并深入了解如何靶向和监测嘧啶生物合成的细胞间调节以促进组织修复。我们使用小分子筛选鉴定了 ENPP1 抑制剂，并表明在心脏损伤后全身给予 ENPP1 抑制剂可以挽救非心肌细胞中的嘧啶生物合成，并增强心脏修复和梗塞后心脏功能。这些观察结果表明，心肌细胞在心脏损伤后通过释放腺嘌呤和特定核苷来调节非肌肉细胞中的嘧啶代谢，并深入了解如何靶向和监测嘧啶生物合成的细胞间调节以促进组织修复。