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.
Highlights
IntroductionIt has been projected that the future socio-economic burden of heart disease will further increase due to aging
It has been projected that the future socio-economic burden of heart disease will further increase due to agingZebrafish can regenerate their adult heart through cardiomyocyte proliferation [2]
Adenovirus (Ad)-mediated transfection of primary postnatal Day 3 (P3) rat cardiomyocytes with a non-functional hCdt1 deletion mutant fused to mCherry (mCherry-hCdt1(30/120)) under the control of the cardiomyocyte-specific α-MHC promoter (Ad-mCherry-hCdt1(30/120) resulted in the expression of mCherry-hCdt1(30/120) in > 90% of neonatal cardiomyocytes based on mCherry staining and counterstaining against cardiomyocyte-specific Troponin I (Supplementary information, Figure S1B-S1D)
Summary
It has been projected that the future socio-economic burden of heart disease will further increase due to aging Zebrafish can regenerate their adult heart through cardiomyocyte proliferation [2]. Several explanations have been put forward including gene silencing [4], DNA damage [5] and centrosome disassembly [6]. While these data suggest that the cell cycle arrest in postnatal cardiomyocytes is permanent, several publications have provided evidence that induction of cardiomyocyte proliferation in the adult mammalian heart improves cardiac function [7,8,9]. Therapy for heart failure is elusive and even in zebrafish, the mechanism of cardiac regeneration is still poorly understood
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