The beta-adrenergic receptors (β-ARs) and catecholamines are present in rodents as early as embryonic day 10.5 (E10.5). However, it is not known whether β-AR signaling plays any role in proliferation and differentiation of ventricular cells in the embryonic heart. Here, we characterized the expression profiles of β-AR subtypes and established dose response curves for a nonselective β-AR agonist isoproterenol (ISO) in the developing mouse ventricular cells. Further, we investigated the effects of ISO on cell cycle activity and differentiation of cultured E11.5 ventricular cells. ISO treatment significantly reduced tritiated thymidine incorporation and cell proliferation rates in both cardiac progenitor cell (CPC) and cardiomyocyte (CM) populations. The ISO mediated effects on DNA synthesis could be abolished by co-treatment of E11.5 cultures with either metoprolol (β1-AR antagonist) or ICI 118, 551 (β2-AR antagonist). In contrast, ISO mediated effects on cell proliferation could be abolished only by metoprolol. Furthermore, ISO treatment significantly increased the percentage of differentiated CMs compared to that in control cultures. Additional experiments revealed that β-AR stimulation leads to downregulation of Erk and Akt phosphorylation levels followed by significant decreases in cyclin D1 and CDK4 levels in E11.5 ventricular cells. Consistent with the in vitro results, we found that chronic stimulation of recipient mice with ISO after intracardiac cell transplantation significantly decreased the graft size while metoprolol protected the grafts from the inhibitory effects of systemic catecholamines. Collectively, these results underscore the effects of β-AR signaling in cardiac development as well as graft expansion post cell transplantation.
- Beta-adrenergic receptor drugs
- Embryonic ventricular cells
- Proliferation and differentiation
- Intracardiac cell transplantation
- Donor cells and drug interactions
- Copyright © 2016, American Journal of Physiology-Heart and Circulatory Physiology