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J. Biol. Chem., Vol. 276, Issue 36, 34206-34212, September 7, 2001
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From the Departments of Arterial smooth muscle cell (SMC) proliferation
contributes to a number of vascular pathologies.
Prostaglandin E2 (PGE2), produced by
the endothelium and by SMCs themselves, acts as a potent SMC growth
inhibitor. The growth-inhibitory effects of PGE2 are
mediated through activation of G-protein-coupled membrane receptors,
activation of adenylyl cyclases (ACs), formation of cAMP, and
subsequent inhibition of mitogenic signal transduction pathways in
SMCs. Of the 10 different mammalian AC isoforms known today, seven
isoforms (AC2-7 and AC9) are expressed in SMCs from various species.
We show that, despite the presence of several different AC isoforms,
the principal AC isoform activated by PGE2 in human
arterial SMCs is a calmodulin kinase II-inhibited AC with
characteristics similar to those of AC3. AC3 is expressed in isolated
human arterial SMCs and in intact aorta. We further show that arterial
SMCs isolated from AC3-deficient mice are resistant to
PGE2-induced growth inhibition. In summary, AC3 is the
principal AC isoform activated by PGE2 in arterial SMCs,
and AC3 mediates the growth-inhibitory effects of PGE2.
Because AC3 activity is inhibited by intracellular calcium through
calmodulin kinase II, AC3 may serve as an important integrator of
growth-inhibitory signals that stimulate cAMP formation and growth
factors that increase intracellular calcium.
Adenylyl Cyclase 3 Mediates Prostaglandin E2-induced
Growth Inhibition in Arterial Smooth Muscle Cells*
,,,§,, and
Pharmacology and
¶ Pathology, University of Washington,
Seattle, Washington 98195
*
This work was supported by National Institutes of Health
Grants HL62887 (to K. E. B.) and NS357056 (to D. R. S.) and by a grant-in-aid from the American Heart Association Northwest Affiliate (to K. E. B). The Central Laboratory for Human Embryology at the University of Washington was supported by National Institutes of Health
Grant HD00836.The costs of publication of this
article were defrayed in part by the
payment of page charges. The article must therefore be hereby marked
"advertisement" in
accordance with 18 U.S.C. Section
1734 solely to indicate this fact.
To whom correspondence should be addressed: Dept. of
Pathology, Box 357470, University of Washington School of Medicine,
Seattle, WA 98195-7470. Tel.: 206-543-1681; Fax: 206-543-3644; E-mail: bornf@u.washington.edu.
Copyright © 2001 by The American Society for Biochemistry and Molecular Biology, Inc.
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