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(Circulation. 2000;102:III-281.)
© 2000 American Heart Association, Inc.
Myocardial Protection and Vascular Biology |
Selective Estrogen Receptor Modulator Idoxifene Inhibits Smooth Muscle Cell Proliferation, Enhances Reendothelialization, and Inhibits Neointimal Formation In Vivo After Vascular Injury
From the Departments of Cardiovascular Pharmacology (T.-L.Y., L.V.-C., J.-L.G., X.L., J.C., B.S., R.W., E.H.O.) and Experimental Toxicology (C.S.L., P.K.N., K.A.G.), SmithKline Beecham Pharmaceuticals, King of Prussia, Pa, and Division of Emergency Medicine, Thomas Jefferson University (X.L.M.), Philadelphia, Pa.
Correspondence to Tian-Li Yue, PhD, Cardiovascular Pharmacology, SB, 709 Swedeland Rd, UW-2510, King of Prussia, PA 19406. E-mail Tian-Li_Yue{at}sbphrd.com
Background—Idoxifene (ID) is a tissue-selective estrogen receptor modulator (SERM). The pharmacological profile of ID in animal studies suggests that it behaves like an estrogen receptor (ER) agonist in bone and lipid metabolism while having negligible ER activity on the reproductive system. It is unknown whether ID retains the vascular protective effects of estrogen.
Methods and Results—In cultured vascular smooth muscle cells
(VSMCs), ID inhibited platelet-derived growth factor–induced DNA
synthesis and mitogenesis with IC50 values of 20.4 and 27.5
nmol/L, respectively. Treatment with ID resulted in S-phase cell cycle
arrest in serum-stimulated VSMCs. ID 1 to 100 nmol/L significantly
protected endothelial cells from tumor necrosis
factor-
(TNF-)–induced apoptosis in vitro. Virgin
Sprague-Dawley rats ovariectomized 1 week before the study were treated
with ID (1 mg · kg-1 ·
d-1) or vehicle by gavage for 3 days before
balloon denudation in carotid artery. The SMC proliferation in injured
vessels was determined by immunostaining for
proliferating cell nuclear antigen (PCNA). The number of PCNA-positive
SMCs was reduced by 69%, 82%, and 86% in the media at days 1, 3 and
7, respectively, and by 78% in the neointima at day 7
after injury in ID- versus vehicle-treated group
(P<0.01). ID significantly enhanced
reendothelialization in the injured carotid arteries as
determined by Evans blue stain and immunohistochemical analysis
for von Willebrand factor. In the former assay, the
reendothelialized area in injured vessels was 43% in
ID-treated group versus 24% in the vehicle group
(P<0.05); in the latter assay, the numbers of von
Willebrand factor–positive cells per cross section increased
from 24.8 (vehicle) to 60.5 (ID) (P<0.01) at day 14
after injury. In addition, the production of nitric oxide from
excised carotid arteries was significantly higher in ID-treated than
the vehicle group (8.5 versus 2.7 nmol/g, P<0.01).
Finally, ID treatment reduced neointimal area and the ratio
of intima to media by 45% and 40%, respectively
(P<0.01), at day 14 after balloon angioplasty.
Conclusions—The results indicate that ID beneficially modulates the balloon denudation–induced vascular injury response. Inhibition of VSMC proliferation and acceleration of endothelial recovery likely mediate this protective effect of ID.
Key Words: idoxifene • vasculature • endothelium • cells • restenosis