Live cell screening platform identifies PPARδ as a regulator of cardiomyocyte proliferation and cardiac repair
| Autor: | Yishu Ding, Kevin Yang, Qinglin Yang, Teayoun Kim, Nicole Dubois, Gilbert Weidinger, Qinqiang Long, Mohankrishna Dalvoy Vasudevarao, Lan He, Felix B. Engel, Nadeera Wickramasinghe, Ajit Magadum, Harsha V Renikunta |
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| Jazyk: | angličtina |
| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
PPARδ TBX20 Tbx20 carbacyclin Rats Sprague-Dawley 03 medical and health sciences Myocyte Animals Myocytes Cardiac PPAR delta Progenitor cell Molecular Biology Zebrafish Cell Proliferation biology Cell growth screening Myocardium GSK3β Cell Biology Cell cycle Zebrafish Proteins biology.organism_classification Epoprostenol 3. Good health Cell biology Rats 030104 developmental biology cardiomyocyte proliferation Immunology cardiac repair Peroxisome proliferator-activated receptor delta Original Article Signal transduction Cardiomyopathies Signal Transduction |
| Zdroj: | Cell Research |
| ISSN: | 1748-7838 1001-0602 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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