From the Division of Cardiovascular Research, St Elizabeth's
Medical Center, Tufts University School of Medicine, Boston, Mass.
Correspondence to Kenneth Walsh, PhD, Division of Cardiovascular Research, St Elizabeth's Medical Center, 736 Cambridge St, Boston, MA 02135-2997. E-mail kwalsh{at}opal.tufts.edu
Background—Nitric oxide (NO)
inhibits vascular smooth muscle cell (VSMC) proliferation and
neointima formation after balloon injury. However, the
molecular mechanisms underlying NO-mediated growth arrest are poorly
understood. In the present study, we examined the effects of the NO
donors sodium nitroprusside (SNP) and
S-nitroso-N-acetylpenicillamine (SNAP) on
cell cycle activity in VSMCs.
Methods and Results—Stimulation of quiescent rat VSMCs with serum
leads to an increase in cyclin-dependent kinase (cdk)2 kinase activity
that correlates with a marked induction of cyclin A protein expression.
The addition of SNP or SNAP to VSMC cultures at the time of serum
stimulation abrogates the induction of cdk2 activity without
suppressing protein levels of cdk2 or cyclin E. These NO donors block
serum-stimulated upregulation of cyclin A mRNA and protein and repress
the serum induction of cyclin A promoter activity in VSMCs.
Conclusions—The addition of the nitric oxide donors SNP or
SNAP to mitogen-stimulated VSMCs prevents activation of cdk2, a key
regulator of the G1 and S phases of the cell cycle. These
NO donors do not affect the expression of cdk2 protein but block the
mitogen-induced expression of cyclin A, an activating subunit of cdk2.
SNP and SNAP also repress the mitogen-stimulated activation of the
cyclin A promoter. These data suggest that the antiproliferative effect
of NO on VSMCs results, at least in part, from the repression of cyclin
A gene transcription.
© 1998 American Heart Association, Inc.
Basic Science Reports
Nitric Oxide–Induced Downregulation of Cdk2 Activity and Cyclin A Gene Transcription in Vascular Smooth Muscle Cells
Key Words: nitric oxide • muscle, smooth • genes
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