© 1995 American Heart Association, Inc.
Articles |
Rapamycin Selectively Inhibits Angiotensin II–Induced Increase in Protein Synthesis in Cardiac Myocytes In Vitro
Potential Role of 70-kD S6 Kinase in Angiotensin II– Induced Cardiac Hypertrophy
From the Cardiovascular Research Center, Division of Cardiology, University of Michigan Medical Center, Ann Arbor.
Correspondence to Dr Seigo Izumo, Cardiovascular Research Center, 7220-MSRB3, University of Michigan Medical Center, Ann Arbor, MI 48109-0644.
Abstract It has been suggested that
phosphorylation of a 40S ribosomal protein, S6,
regulates protein synthesis. Two distinct families of S6 kinase have
been identified, the rsk-encoded 85- to 92-kD S6 kinase
(RSK) and the 70- or 85-kD S6 kinase (p70S6K). We have
previously shown that hypertrophic stimuli, such as
angiotensin II (Ang II), rapidly activate RSK in
cardiac myocytes. However, RSK and p70S6K are regulated by
distinct mechanisms, and p70S6K, but not RSK, is the
physiological S6 kinase in vivo in other cell
types. Using cultured neonatal rat ventricular myocytes, we
examined whether Ang II activates p70S6K and
investigated the effect of rapamycin, a potent yet indirect
inhibitor of p70S6K, on the Ang
II–induced hypertrophic response. Immunoblot
analyses indicate that cardiac myocytes express the 70- and
85-kD forms of p70S6K. Ang II caused a rapid and sustained
activation of p70S6K through the type I Ang II receptor.
Rapamycin inhibited Ang II–induced activation of p70S6K in
a dose-dependent manner, with an IC50 of 0.14 ng/mL
(0.15 nmol/L). Rapamycin did not inhibit Ang II–induced activation of
tyrosine kinase, mitogen-activated protein kinase, RSK, and
protein kinase C. The effect of rapamycin is unlikely to be mediated by
its effect on p34cdc2 and p33cdk2 because Ang
II did not activate these cell cycle–dependent kinases in
cardiac myocytes. In contrast, a dose-dependent inhibition of
p70S6K by rapamycin is very closely correlated with its
inhibition of the Ang II–induced increase in protein synthesis.
Interestingly, rapamycin did not affect the Ang II–induced activation
of specific gene expression, including the immediate-early gene
c-fos and fetal type genes, such as atrial
natriuretic factor and skeletal 
-actin. Moreover,
rapamycin did not suppress Ang II–induced phenotypic changes at the
protein level, such as increased atrial natriuretic factor
secretion, expression of ß-myosin heavy chain, and organization
of actin into sarcomeric units. These results indicate that
p70S6K is activated by Ang II and that a
rapamycin-sensitive signaling mechanism, most likely
p70S6K, plays an essential role in the Ang
II–induced increase in overall protein synthesis but not in Ang
II–induced specific phenotypic changes in cardiac myocytes.
Key Words: cardiac hypertrophy • 70-kD S6 kinase • angiotensin II • protein synthesis • rapamycin
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