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Vol. 300, Issue 3, 1101-1110, March 2002
Department of Pharmacology, College of Medicine, University of
Arizona, Tucson, Arizona (V.C.T., Q.M.C.); and The Sarver Heart Center,
University of Arizona, Arizona Health Science Center, Tucson, Arizona
(J.J.B.)
Cardiomyocytes in culture can survive low or mild doses of oxidants but
later increase cell volume and protein content. To understand the
mechanism, we determined the early signaling events of oxidative
stress. With 200 µM H2O2, the activity of p70
S6 kinase-1 (p70S6K1) increased at 30 min and reached a plateau at 90 min. Dose-response studies at the 60 min time point show that p70S6K1
activity reached its highest level with 150 µM
H2O2. Increased p70S6K1 activity correlated
with phosphorylation of Thr389 and Thr421/Ser424 residues, suggesting
the involvement of an upstream kinase. Phosphoinositide 3-kinase (PI3K)
activity was elevated by 5 min, reached a plateau at 10 min, and
remained more than 6-fold induced for at least 60 min after 200 µM
H2O2 exposure. The dose-response studies at 10 min found that 150 µM H2O2 induced the
highest PI3K activity. Increased PI3K activity correlated with tyrosine
phosphorylation of the 85-kDa regulatory subunit. Inactivating PI3K
with wortmannin prevented H2O2 from inducing Thr389 phosphorylation and p70S6K1 activation. Wortmannin and rapamycin
prevented H2O2 from inducing increases in cell
volume and protein content. The antineoplastic drugs doxorubicin and daunorubicin also induced significant enlargement of cardiomyocytes at
10 to 100 nM dose range. Although the glutathione synthesis inhibitor
buthionine sulfoximine potentiated the effect of doxorubicin and
H2O2, the antioxidant
N-acetylcysteine prevented induction of cell
enlargement. Our data suggest that oxidative stress induces activation
of PI3K, which leads to p70S6K1 activation and enlargement of cell size.
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