Zebrafish can efficiently regenerate their heart through cardiomyocyte proliferation. In contrast, mammalian cardiomyocytes stop proliferating shortly after birth, limiting the regenerative capacity of the postnatal mammalian heart. Therefore, if the endogenous potential of postnatal cardiomyocyte proliferation could be enhanced, it could offer a promising future therapy for heart failure patients. Here, we set out to systematically identify small molecules triggering postnatal cardiomyocyte proliferation. By screening chemical compound libraries utilizing a Fucci-based system for assessing cell cycle stages, we identified carbacyclin as an inducer of postnatal cardiomyocyte proliferation. In vitro, carbacyclin induced proliferation of neonatal and adult mononuclear rat cardiomyocytes via a peroxisome proliferator-activated receptor δ (PPARδ)/PDK1/p308Akt/GSK3β/β-catenin pathway. Inhibition of PPARδ reduced cardiomyocyte proliferation during zebrafish heart regeneration. Notably, inducible cardiomyocyte-specific overexpression of constitutively active PPARδ as well as treatment with PPARδ agonist after myocardial infarction in mice induced cell cycle progression in cardiomyocytes, reduced scarring, and improved cardiac function. Collectively, we established a cardiomyocyte proliferation screening system and present a new drugable target with promise for the treatment of cardiac pathologies caused by cardiomyocyte loss.

中文翻译：

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活细胞筛选平台将 PPARδ 鉴定为心肌细胞增殖和心脏修复的调节剂。


斑马鱼可以通过心肌细胞增殖有效地再生心脏。相比之下，哺乳动物心肌细胞在出生后不久就停止增殖，限制了出生后哺乳动物心脏的再生能力。因此，如果能够增强出生后心肌细胞增殖的内源性潜力，则可以为心力衰竭患者提供有希望的未来治疗方法。在这里，我们着手系统地识别触发出生后心肌细胞增殖的小分子。通过利用基于 Fucci 的系统评估细胞周期阶段筛选化合物库，我们确定卡巴环素是出生后心肌细胞增殖的诱导剂。在体外，碳环素通过过氧化物酶体增殖物激活受体 δ (PPARδ)/PDK1/p308Akt/GSK3β/β-catenin 途径诱导新生和成年单核大鼠心肌细胞增殖。抑制 PPARδ 可减少斑马鱼心脏再生过程中心肌细胞的增殖。值得注意的是，诱导性心肌细胞特异性过度表达组成型活性 PPARδ 以及在小鼠心肌梗死后使用 PPARδ 激动剂治疗可诱导心肌细胞的细胞周期进展，减少疤痕形成并改善心脏功能。总的来说，我们建立了心肌细胞增殖筛选系统，并提出了一个新的药物靶点，有望治疗由心肌细胞丢失引起的心脏病。