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Cell Res. 2017 Aug;27(8):1002-1019. doi: 10.1038/cr.2017.84. Epub 2017 Jun 16.

Live cell screening platform identifies PPARδ as a regulator of cardiomyocyte proliferation and cardiac repair.

Author information

1
Department of Cardiac Development and Remodelling, Max-Planck-Institute for Heart and Lung Research, Parkstrasse 1, Bad Nauheim 61231, Germany.
2
Department of Cardiology, Icahn School of Medicine at Mount Sinai Hospital, One Gustave L. Levy Place, Box 1030, New York, NY 10029, USA.
3
Department of Nutrition Sciences, University of Alabama at Birmingham, 1675 University Blvd, Birmingham, AL 35294-3360, USA.
4
Institute of Biochemistry and Molecular Biology, Ulm University, Albert-Einstein-Allee 11, Ulm 89081, Germany.
5
Division of Cardiology, Department of Internal Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Ave, Wuhan, Hubei 430030, China.
6
Department for Cell, Developmental and Regenerative Biology, Icahn School of Medicine at Mount Sinai, 1470 Madison Avenue, Box 1040, New York, NY 10029, USA.
7
Department of Nephropathology, Experimental Renal and Cardiovascular Research, Institute of Pathology, Friedrich-Alexander-Universität Erlangen-Nürnberg, Schwabachanlage 12, Erlangen 91054, Germany.
8
Muscle Research Center Erlangen (MURCE).

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.

PMID:
28621328
PMCID:
PMC5539351
DOI:
10.1038/cr.2017.84
[Indexed for MEDLINE]
Free PMC Article

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