© 1996 American Heart Association, Inc.
Articles |
Extracellular ATP Inhibits Adrenergic Agonist–Induced Hypertrophy of Neonatal Cardiac Myocytes
From the Laboratory of Cardiovascular Science, National Institute on Aging, National Institutes of Health, Baltimore, Md.
Correspondence to Michael T. Crow, PhD, Laboratory of Cardiovascular Science, National Institute on Aging, National Institutes of Health, Gerontology Research Center, 4940 Eastern Ave, Baltimore, MD 21224.
Abstract We have previously shown that extracellular ATP,
like norepinephrine (NE) and many other
hypertrophyinducing 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
-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.
Key Words: ATP • purinergic receptors • cardiac hypertrophy • norepinephrine • cardiac myocytes
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