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1 Programme in Cell Biology, The Hospital for Sick Children, Toronto, Ontario, Canada M5G 1X8; and 2 Department of Woman and Child Health, Pediatric Unit, Astrid Lindgren Children's Hospital, Karolinska Hospital, S-171 76 Stockholm, Sweden
The activity of
the
Na+-K+-pump
is intricately linked to the maintenance of vascular tone. Here we
demonstrate that insulin-like growth factor I (IGF-I) increases
Na+-K+-pump
activity in the vascular smooth muscle cell (VSMC) clone A7r5 in a
time- and dose-dependent manner. This stimulatory effect of IGF-I was
prevented by the tyrosine kinase inhibitor genistein (5 µM) and by
the specific phosphatidylinositol 3-kinase (PI3K) inhibitors wortmannin
(100 nM) and LY-294002 (25 µM). IGF-I activated a
wortmannin-sensitive PI3K and its purported effector, the atypical protein kinase C (PKC)-
. Stimulation of PKC- was
prevented by the generic PKC inhibitor GF109203x (bisindolylmaleimide,
10 µM). Downregulation of diacylglycerol-sensitive (conventional and
novel) PKCs by 24-h pretreatment with 1 µM phorbol 12-myristate
13-acetate had no effect on IGF-I-stimulated
Na+-K+-pump
activity. Similarly, inhibition of only conventional and novel PKCs
with GF109203x (1 µM) had no effect on IGF-I-stimulated Na+-K+-pump
activity. In contrast, a concentration of GF109203x (10 µM) that also
inhibits the atypical PKCs abolished
Na+-K+-pump
stimulation by IGF-I. Neither the
Na+-K+-2Cl
cotransporter inhibitor bumetanide (100 µM) nor the
Na+/H+
exchanger inhibitor HOE-694 (5 µM) affected the
Na+-K+-pump
stimulation by IGF-I, suggesting that a rise in intracellular Na+ concentration is not necessary
for increased
Na+-K+-pump
activity. These results suggest that IGF-I directly stimulates the
Na+-K+
pump via a signaling pathway involving PI3K and atypical PKC ().
sodium-potassium adenosine 5'-triphosphatase; tyrosine kinase; vascular resistance
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