ZFIN ID: ZDB-PUB-170618-14
Live cell screening platform identifies PPARδ as a regulator of cardiomyocyte proliferation and cardiac repair
Magadum, A., Ding, Y., He, L., Kim, T., Vasudevarao, M.D., Long, Q., Yang, K., Wickramasinghe, N., Renikunta, H.V., Dubois, N., Weidinger, G., Yang, Q., Engel, F.B.
Date: 2017
Source: Cell Research   27(8): 1002-1019 (Journal)
Registered Authors: Weidinger, Gilbert
Keywords: cardiac repair, cardiomyocyte proliferation, screening, carbacyclin, PPARδ, GSK3β, Tbx20
MeSH Terms:
  • Animals
  • Cardiomyopathies/drug therapy
  • Cardiomyopathies/metabolism*
  • Cardiomyopathies/pathology
  • Cell Proliferation/drug effects*
  • Epoprostenol/analogs & derivatives*
  • Epoprostenol/pharmacology
  • Myocardium/metabolism*
  • Myocardium/pathology
  • Myocytes, Cardiac/metabolism*
  • Myocytes, Cardiac/pathology
  • PPAR delta/metabolism*
  • Rats
  • Rats, Sprague-Dawley
  • Signal Transduction/drug effects*
  • Zebrafish/embryology*
  • Zebrafish Proteins/metabolism*
PubMed: 28621328 Full text @ Cell Res.
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ABSTRACT
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.Cell Research advance online publication 16 June 2017; doi:10.1038/cr.2017.84.
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