(Circulation. 2000;102:2124.)
© 2000 American Heart Association, Inc.
Basic Science Reports |
Inhibition of Vascular Smooth Muscle Cell Proliferation by Sodium Salicylate Mediated by Upregulation of p21Waf1 and p27Kip1
From the Cardiovascular Division, Brigham & Women’s Hospital and Harvard Medical School, Boston, Mass.
Correspondence to James K. Liao, MD, Cardiovascular Division, 221 Longwood Ave, LMRC-322, Boston, MA 02115. E-mail jliao{at}rics.bwh.harvard.edu
Background—Salicylates may have direct vascular effects by mechanisms that are independent of platelet inhibition.
Methods and Results—We investigated the effect of salicylates on
vascular smooth muscle cell (SMC) proliferation in response to
platelet-derived growth factor (PDGF) in vitro. Salicylate
concentrations of 5 and 10 mmol/L inhibited serum- or PDGF-induced
SMC cell count and [3H]thymidine incorporation by 62%
and 81%, respectively. There was no evidence of cellular toxicity or
apoptosis as determined by trypan blue exclusion and FACS
analyses. Because cell cycle progression is regulated by
hyperphosphorylation of the retinoblastoma (Rb)
protein, we examined the effects of salicylate on Rb
hyperphosphorylation. Treatment with salicylate, but
not indomethacin, inhibited nuclear factor-
B
activation and completely abolished Rb
hyperphosphorylation in PDGF-treated SMCs. This effect
was associated with a decrease in cyclin-dependent kinase (Cdk)-2 and,
to a lesser extent, Cdk-6, but not Cdk-4 activity, without changes in
Cdk-2, -4, and -6 and cyclin D and E protein levels. Because Cdk-2
activity is regulated by the Cdk inhibitors
p21Waf1 and p27Kip1, we studied the effects of
salicylate on p21Waf1 and p27Kip1 expression.
Treatment with salicylate prevented PDGF-induced downregulation of
p21Waf1 and p27Kip1 but not of the Cdk-4/-6
inhibitor p16Ink4.
Conclusions—These findings indicate that high doses of salicylates inhibit SMC proliferation by cell cycle arrest at the G1-S phase and suggest a beneficial role for high-dose salicylates in the treatment of vascular proliferative disorders.
Key Words: aspirin • cells • muscle, smooth • proteins • kinases
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