Cardiomyocytes disrupt pyrimidine biosynthesis in nonmyocytes to regulate heart repair.
Cardiomyocytes disrupt pyrimidine biosynthesis in nonmyocytes to regulate heart repair.
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心肌细胞干扰非心肌细胞中的嘧啶生物合成以调节心脏修复。
DOI：
10.1172/jci149711
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发表时间：
2022-01-18
期刊：
影响因子：
--
通讯作者：
Deb A
中科院分区：
文献类型：
--
作者：
Li S;Yokota T;Wang P;Ten Hoeve J;Ma F;Le TM;Abt ER;Zhou Y;Wu R;Nanthavongdouangsy M;Rodriguez A;Wang Y;Lin YJ;Muranaka H;Sharpley M;Braddock DT;MacRae VE;Banerjee U;Chiou PY;Seldin M;Huang D;Teitell M;Gertsman I;Jung M;Bensinger SJ;Damoiseaux R;Faull K;Pellegrini M;Lusis AJ;Graeber TG;Radu CG;Deb A
心脏损伤后多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。利用缺血性心脏损伤的小鼠模型，我们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起关键作用。心脏损伤诱导外切核苷酸酶——外切核苷酸焦磷酸酶/磷酸二酯酶1（ENPP1）的表达，该酶水解细胞外ATP形成AMP。对AMP作出反应，心肌细胞释放腺嘌呤和特定的核糖核苷，这些物质在乳清酸核苷单磷酸（OMP）合成步骤干扰嘧啶生物合成，并诱导遗传毒性应激以及p53介导的增殖性非心肌细胞死亡。由于非心肌细胞对心脏修复至关重要，我们表明通过给予尿苷或对ENPP1/AMP通路进行基因靶向来挽救嘧啶生物合成可增强心脏损伤后的修复。我们通过小分子筛选确定了ENPP1抑制剂，并表明心脏损伤后全身给予ENPP1抑制剂可挽救非心肌细胞中的嘧啶生物合成，增强心脏修复和梗死后心脏功能。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，并为如何针对和监测嘧啶生物合成的细胞间调节以增强组织修复提供了见解。
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.
影响因子：
3.5
作者：
Moeller, Sina;Jung, Caroline;Adriouch, Sahil;Dubberke, Gudrun;Seyfried, Fabienne;Seman, Michel;Haag, Friedrich;Koch-Nolte, Friedrich
通讯作者：
Koch-Nolte, Friedrich