Live cell screening platform identifies PPAR? as a regulator of cardiomyocyte proliferation and cardiac repair

Magadum A, Ding Y, He L, Kim T, Vasudevarao MD, Long Q, Yang K, Wickramasinghe N, Renikunta HV, Dubois N, Weidinger G, Yang Q, Engel F (2017)

Publication Type: Journal article

Publication year: 2017

Journal

Cell Research Nature Publishing Group: Open Access Hybrid Model Option B

Book Volume: 27

Pages Range: 1002-1019

Journal Issue: 8

DOI: 10.1038/cr.2017.84

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 ? (PPAR?)/PDK1/p308Akt/GSK3?/?-catenin pathway. Inhibition of PPAR? reduced cardiomyocyte proliferation during zebrafish heart regeneration. Notably, inducible cardiomyocyte-specific overexpression of constitutively active PPAR? as well as treatment with PPAR? 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.

Authors with CRIS profile

Felix Engel Professur für Experimentelle Nieren- und Kreislaufforschung

Involved external institutions

University of Alabama at Birmingham (UAB) US United States (USA) (US) Universität Ulm DE Germany (DE) Icahn School of Medicine at Mount Sinai US United States (USA) (US) Max Planck Institute for Heart and Lung Research / Max-Planck-Institut für Herz- und Lungenforschung DE Germany (DE)

How to cite

APA:

Magadum, A., Ding, Y., He, L., Kim, T., Vasudevarao, M.D., Long, Q.,... Engel, F. (2017). Live cell screening platform identifies PPAR? as a regulator of cardiomyocyte proliferation and cardiac repair. Cell Research, 27(8), 1002-1019. https://doi.org/10.1038/cr.2017.84

MLA:

Magadum, Ajit, et al. "Live cell screening platform identifies PPAR? as a regulator of cardiomyocyte proliferation and cardiac repair." Cell Research 27.8 (2017): 1002-1019.

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