Beta-adrenergic stimulation of cardiac non-myocytes augments the growth-promoting activity of non-myocyte conditioned medium

Abstract

Although the stimulatory action of catecholamines on the heart has been presumed to result exclusively from their direct effects on the cardiac myocytes, little work has been done addressing the effects of catecholamines on the supporting non-myocytes of the heart. We have recently identified medium conditioned by neonatal rat cardiac non-myocytes (NMC-CM) as the source of a growth-promoting factor which leads to cardiac myocyte hypertrophy in culture, suggesting that these non-myocytes may play an active role in myocardial growth. Since cardiac non-myocytes also contain adrenergic receptors (both alpha and beta) on their cell surface, we asked whether adrenergic stimulation of these non-myocytes could supplement the growth-promoting effect of NMC-CM. While isoproterenol (ISO, 0.2 microM) caused no increase in the per cell content of total protein in the non-myocytes, inclusion of ISO in the medium used in the production of NMC-CM augmented the growth promoting effects of this "ISOCM" over control CM. This increase was not seen with the alpha 1 adrenergic agonist phenylephrine suggesting that the stimulatory effect was specific to the beta-adrenergic receptor. Because TGF beta 3 contains an upstream cAMP Response Element, we wonder whether its expression could respond to the increase in cAMP induced by ISO. Non-myocytes treated over 72 h with ISO expressed increased steady state mRNA levels for TGF beta 3 but not that for the closely related TGF beta 1 over this time period. We believe that this is the first report indicating that a potential mechanism for the observed effects of beta-adrenergic stimulation on myocardial cells in culture and possibly relevant in vivo is the contribution of beta-stimulated factor(s) produced by non-myocytes which act in a paracrine fashion on myocardial cells.