Abstract
Little is known regarding factors that induce parasympathetic responsiveness during cardiac development. We demonstrated previously that in atrial cells cultured from chicks 14 days in ovo, transforming growth factor beta (TGFbeta) decreased parasympathetic inhibition of beat rate by the muscarinic agonist, carbamylcholine, by 5-fold and decreased expression of Galpha(i2). Here in atrial cells 5 days in ovo, TGFbeta increased carbamylcholine inhibition of beat rate 2.5-fold and increased expression of Galpha(i2). TGFbeta also stimulated Galpha(i2) mRNA expression and promoter activity at day 5 while inhibiting them at day 14 in ovo. Over the same time course expression of type I TGFbeta receptors, chick activin receptor-like kinase 2 and 5 increased with a 2.3-fold higher increase in activin receptor-like kinase 2. Constitutively active activin receptor-like kinase 2 inhibited Galpha(i2) promoter activity, whereas constitutively active activin receptor-like kinase 5 stimulated Galpha(i2) promoter activity independent of embryonic age. In 5-day atrial cells, TGFbeta stimulated the p3TP-lux reporter, which is downstream of activin receptor-like kinase 5 and had no effect on the activity of the pVent reporter, which is downstream of activin receptor-like kinase 2. In 14-day cells, TGFbeta stimulated both pVent and p3TP-lux. Thus TGFbeta exerts opposing effects on parasympathetic response and Galpha(i2) expression by activating different type I TGFbeta receptors at distinct stages during cardiac development.
Highlights
Little is known regarding factors that induce parasympathetic responsiveness during cardiac development
To determine the effect of TGF on the development of the parasympathetic response, embryonic chick atrial cells from 5 dio hearts were incubated for 16 h with either 5 ng/ml transforming growth factor  (TGF)1 or vehicle, and beat rate was determined in the presence of carbamylcholine
TGF1 increases the chronotropic response to carbamylcholine by more than 2.5-fold in atrial myocytes from hearts 5 dio. This result is opposite to the effect of TGF1 in cells from atria of hearts 14 dio in which we demonstrated that TGF1 decreased the chronotropic response to carbamylcholine by more than 5-fold (Table I) [7]
Summary
TGF, transforming growth factor ; TBRI, type I TGF receptor; TBRII, type II TGF receptor; ActRII, type II activin receptor; BMP, bone morphogenic protein; BMPRII, type II BMP receptor; GAPDH, glyceraldehyhyde phosphate dehydrogenase; ALK, activin receptor-like kinase; chALK, chick ALK; chALKϩ, constitutively active chALK; PAP, placental alkaline phosphatase; dio, days in ovo; Luc, luciferase; PAI-1, plasminogen activator inhibitor; pBS, pBluescript. TGF Type I Receptor Activation in the Heart receptors for activin (ActRII and ActRIIB) and BMP (BMPRII). ALK2 interacts with TBRII as well as ActRII and BMPRII type II receptors [12]. ALK2 does not mediate TGF signaling in mink lung epithelial cells but has been implicated in the TGF-stimulated epithelial-mesenchymal transformation in the mammary gland of the mouse [13]. The regulation of TGF receptor signaling by selective interactions with different type I receptors is an intriguing mechanism that might help explain the pleiotropic effects of TGF. We demonstrate that TGF mediates opposing effects on G␣i2 expression and the response of the heart to parasympathetic stimulation at different stages of chick heart development and that these pleiotropic effects are due to differential activation of ALK2 and ALK5 by TGF
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