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1 The Cardiovascular Institute and the Departments of 2 Physiology and 3 Medicine, Loyola University Chicago Stritch School of Medicine, Maywood, Illinois 60153
Agonist-induced
hypertrophy of cultured neonatal rat ventricular myocytes (NRVM) has
been attributed to biochemical signals generated during receptor
activation. However, NRVM hypertrophy can also be induced by
spontaneous or electrically stimulated contractile activity in the
absence of exogenous neurohormonal stimuli. Using single-cell imaging
of fura 2-loaded myocytes, we found that low-density, noncontracting
NRVM begin to generate intracellular
Ca2+ concentration
([Ca2+]i)
transients and contractile activity within minutes of exposure to the
1-adrenergic agonist
phenylephrine (PE; 50 µM). However, NRVM pretreated with verapamil
and then stimulated with PE failed to elicit
[Ca2+]i
transients and beating. We therefore examined whether PE-induced [Ca2+]i
transients and contractile activity were required to elicit specific
aspects of the hypertrophic phenotype. PE treatment (48-72 h)
increased cell size, total protein content, total protein-to-DNA ratio,
and myosin heavy chain (MHC) isoenzyme content. PE also stimulated
sarcomeric protein assembly and prolonged MHC half-life. However,
blockade of voltage-gated L-type
Ca2+ channels with verapamil,
diltiazem, or nifedipine (10 µM) blocked PE-induced total protein and
MHC accumulation and prevented the time-dependent assembly of
myofibrillar proteins into sarcomeres. Inhibition of actin-myosin
cross-bridge cycling with 2,3-butanedione monoxime (7.5 mM) also
prevented PE-induced total protein and MHC accumulation, indicating
that mechanical activity, rather than
[Ca2+]i
transients per se, was required. In contrast, blockade of
[Ca2+]i
transients and contractile activity did not prevent the PE-induced increase in cell surface area, activation of the mitogen-activated protein kinases ERK1 and ERK2, or upregulation of atrial natriuretic factor gene expression. Thus contractile activity is required to elicit
some but not all aspects of the the hypertrophic phenotype induced by
1-adrenergic receptor
activation.
calcium; verapamil; signal transduction; fura 2; gene expression; cytoskeleton
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