title: Extracellular ATP inhibits adrenergic agonist-induced hypertrophy of neonatal cardiac myocytes.
abstract: We have previously shown that extracellular ATP, like norepinephrine (NE) and many other hypertrophy-inducing agents, increases expression of the immediate-early genes c-fos and junB in cultured neonatal cardiac myocytes but that the intracellular signaling pathways activated by ATP and responsible for these changes differ from those stimulated by NE. Furthermore, whereas NE increases incorporation of [14C]phenylalanine (14C-Phe) and cell size in neonatal cardiomyocytes, ATP does not. Since ATP is coreleased with NE from sympathetic nerve endings in the heart, we investigated whether ATP could modulate cardiac hypertrophy induced by adrenergic agonists, such as NE. We report in the present study that extracellular ATP inhibited the increase in incorporation of 14C-Phe into cellular protein and the increase in cell size in neonatal rat cardiac myocytes that was induced by NE, phenylephrine (PE), basic fibroblast growth factor, or endothelin-1. This inhibition was dose dependent, occurred predominantly through P2 purinergic receptors, and was observed even when cells were treated with ATP for as little as 1 hour before the addition of the hypertrophy-inducing agent. ATP also selectively affected changes in gene expression associated with hypertrophy. It prevented PE-stimulated increases in atrial natriuretic factor and myosin light chain-2 mRNA levels, while appearing to augment basal and PE-stimulated skeletal alpha-actin mRNA levels. ATP alone increased sarcoplasmic reticulum Ca2+-ATPase mRNA levels but had no effect when added with PE. ATP did not significantly affect the level of the constitutively expressed mRNA for GAPDH. Neither the PE-stimulated increase in immediate-early gene expression nor the initial induction of mitogen-activated protein kinase activity by PE was inhibited by ATP. These results demonstrate that extracellular ATP can inhibit hypertrophic growth of neonatal cardiac myocytes and differentially alter the changes in gene expression that accompany hypertrophy.
authors.affiliation: Laboratory of Cardiovascular Science, National Institute on Aging, National Institutes of Health, Baltimore, MD, 21224, USA.
authors.forename: J S
authors.initials: JS
authors.lastname: Zheng
authors.forename: M O
authors.initials: MO
authors.lastname: Boluyt
authors.forename: X
authors.initials: X
authors.lastname: Long
authors.forename: L
authors.initials: L
authors.lastname: O'Neill
authors.forename: E G
authors.initials: EG
authors.lastname: Lakatta
authors.forename: M T
authors.initials: MT
authors.lastname: Crow
mesh_terms: D000255:Adenosine Triphosphate / Q000494:pharmacology / Q000502:physiology*; D000322:Adrenergic Agonists; D018674:Adrenergic Antagonists / Q000494:pharmacology*; D000818:Animals; D000831:Animals, Newborn; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000378:metabolism; D002250:Carbon Radioisotopes; D006332:Cardiomegaly / Q000139:chemically induced* / Q000235:genetics / Q000517:prevention & control*; D048429:Cell Size / Q000187:drug effects; D002478:Cells, Cultured; D002851:Chromatography, High Pressure Liquid; D005110:Extracellular Space / Q000737:chemistry*; D015870:Gene Expression / Q000187:drug effects; D016762:Genes, fos; D006352:Heart Ventricles; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases; D015335:Molecular Probes / Q000235:genetics; D008969:Molecular Sequence Data; D009206:Myocardium / Q000166:cytology / Q000378:metabolism; D010649:Phenylalanine / Q000378:metabolism / Q000494:pharmacology; D010656:Phenylephrine / Q000494:pharmacology; D011494:Protein Kinases / Q000187:drug effects / Q000378:metabolism; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar
chemical_list: D000322:Adrenergic Agonists; D018674:Adrenergic Antagonists; D002250:Carbon Radioisotopes; D015335:Molecular Probes; D010656:Phenylephrine; D010649:Phenylalanine; D000255:Adenosine Triphosphate; D011494:Protein Kinases; D011505:Protein-Tyrosine Kinases; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases