title: UTP transactivates epidermal growth factor receptors and promotes cardiomyocyte hypertrophy despite inhibiting transcription of the hypertrophic marker gene, atrial natriuretic peptide.
abstract: In neonatal rat ventricular myocytes, activation of receptors that couple to the G(q) family of heterotrimeric G proteins causes hypertrophic growth, together with expression of "hypertrophic marker" genes, such as atrial natriuretic peptide (ANP) and myosin light chain 2 (MLC2). As reported previously for other G(q)-coupled receptors, stimulation of alpha(1)-adrenergic receptors with phenylephrine (50 microM) caused phosphorylation of epidermal growth factor (EGF) receptors as well as activation of ERK1/2, cellular growth, and ANP transcription. These responses depended on EGF receptor activation. In marked contrast, stimulation of G(q)-coupled purinergic receptors with UTP caused EGF receptor phosphorylation, ERK1/2 activation, and cellular growth but minimal increases in ANP transcription. UTP inhibited phenylephrine-dependent transcription from ANP and MLC2 promoters but not transcription from myoglobin promoters or from AP-1 elements. Myocardin is a muscle-specific transcription enhancer that activates transcription from ANP and MLC2 promoters but not myoglobin promoters or AP-1 elements. UTP inhibited ANP and MLC2 responses to overexpressed myocardin but did not inhibit responses to c-Jun, GATA4, or serum response factor, all of which are active in nonmuscle cells. Thus, UTP inhibits transcriptional responses to phenylephrine only at cardiac-specific promoters, and this may involve the muscle-specific transcription enhancer, myocardin. These studies show that EGF receptor activation is necessary but not sufficient for ANP and MLC2 responses to activation of G(q)-coupled receptors in ventricular myocytes, because inhibitory mechanisms can oppose such stimulation. ANP is a compensatory and protective factor in cardiac hypertrophy, and mechanisms that reduce its generation need to be defined.
authors.affiliation: Cellular Biochemistry Laboratory, Baker Heart Research Institute, St. Kilda Road Central, Melbourne, 8008 Victoria, Australia.
authors.forename: James B
authors.initials: JB
authors.lastname: Morris
authors.forename: Tam M
authors.initials: TM
authors.lastname: Pham
authors.forename: Bronywn
authors.initials: B
authors.lastname: Kenney
authors.forename: Karen E
authors.initials: KE
authors.lastname: Sheppard
authors.forename: Elizabeth A
authors.initials: EA
authors.lastname: Woodcock
mesh_terms: D000818:Animals; D009320:Atrial Natriuretic Factor / Q000037:antagonists & inhibitors* / Q000235:genetics; D006332:Cardiomegaly / Q000209:etiology / Q000378:metabolism / Q000473:pathology; D066246:ErbB Receptors / Q000187:drug effects / Q000502:physiology*; D032383:Myocytes, Cardiac / Q000473:pathology / Q000502:physiology*; D011401:Promoter Regions, Genetic; D051381:Rats; D017207:Rats, Sprague-Dawley; D015533:Transcriptional Activation / Q000187:drug effects; D014544:Uridine Triphosphate / Q000494:pharmacology*
chemical_list: D009320:Atrial Natriuretic Factor; D066246:ErbB Receptors; D014544:Uridine Triphosphate