© 1997 American Heart Association, Inc.
Articles |
Rapamycin Inhibits 
1-Adrenergic Receptor–Stimulated Cardiac Myocyte Hypertrophy but Not Activation of Hypertrophy-Associated Genes
Evidence for Involvement of p70 S6 Kinase
From the Laboratory of Cardiovascular Science (M.O.B., J-S.Z., X.L., L.O., E.G.L., M.T.C.), Gerontology Research Center, National Institute on Aging, National Institutes of Health, Baltimore, Md; Département de Biologie Appliquée (A.Y.), Institut Universitaire de Technologie de Clermont-Ferrand, Aubière, France; and the Division of Cardiology (H.S.), Johns Hopkins Hospital, Baltimore, Md.
Correspondence to Marvin O. Boluyt, PhD, Laboratory of Cardiovascular Science, National Institute on Aging, Gerontology Research Center, 4940 Eastern Ave, Baltimore, MD 21224. E-mail marvinb{at}vax.grc.nia.nih.gov
Abstract The 70-kD S6 kinase (p70S6K) has been
implicated in the regulation of protein synthesis in many cell types
and in the angiotensin II–stimulated
hypertrophy of cardiac myocytes. Our purpose was to
determine whether p70S6K plays a role in
cardiomyocyte hypertrophy induced by the
1-adrenergic receptor (1-AR) agonist
phenylephrine (PE). PE stimulated the activity of
p70S6K >3-fold, and this increase was blocked by
rapamycin, an immunosuppressant macrolide that selectively inhibits
p70S6K. When administered for 3 days, PE stimulated a 30%
increase in total protein content, a 2-fold increase in the
incorporation of [14C]phenylalanine (14C-Phe)
into protein, and a 50% increase in two-dimensional myocyte area.
Rapamycin pretreatment (
500 pg/mL) significantly inhibited each of
these PE-stimulated changes. Two days of PE treatment resulted in a
1.6-fold increase in total RNA yield per dish, a 2-fold increase in
incorporation of [14C]uridine into myocyte RNA, and
increases in relative mRNA levels of the
hypertrophy-associated atrial natriuretic
factor (ANF, 2.1-fold) and skeletal -actin (SK, 2.2-fold) genes.
Although rapamycin abolished the PE-stimulated increases in total RNA
and incorporation of [14C]uridine, it had no effect on
the induction of the ANF and SK genes. LY294002, a specific
inhibitor of phosphatidylinositol 3-kinase (PI3-K)
activity, inhibited PE-stimulated increases in p70S6K
activity and the incorporation of labeled precursors into myocyte
protein and RNA. These results demonstrate that p70S6K is
activated by the hypertrophic agent PE and that a PI3-K or
PI3-K–like activity is required for p70S6K activation and
myocyte hypertrophy. The data suggest that
p70S6K activation may be required for PE-stimulated
hypertrophy of cardiac myocytes. Our results demonstrate
that intracellular signaling pathways responsible for transcriptional
and translational responses diverge early after 1-AR
stimulation in cardiac myocytes.
Key Words: ribosomal S6-kinase • 1-adrenergic receptor • immunosuppressant drug • rapamycin • phosphatidylinositol-3 kinase
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