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Intimal hyperplasia following vascular injury is not inhibited by an antisense thrombin receptor oligodeoxynucleotide
Author(s) -
Herbert J. M.,
Guy A. F.,
Lamarche I.,
Mares A. M.,
Savi P.,
Dol F.
Publication year - 1997
Publication title -
journal of cellular physiology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.529
H-Index - 174
eISSN - 1097-4652
pISSN - 0021-9541
DOI - 10.1002/(sici)1097-4652(199702)170:2<106::aid-jcp2>3.0.co;2-s
Subject(s) - thrombin , thrombin receptor , sense (electronics) , receptor , vascular smooth muscle , intimal hyperplasia , in situ hybridization , chemistry , neointima , microbiology and biotechnology , endocrinology , biology , medicine , messenger rna , biochemistry , restenosis , smooth muscle , gene , platelet , stent
Thrombin is a multifunctional serine protease with central functions in hemostasis, but demonstration of its role in the initiation and maintenance of cell proliferation which occurs following vascular injury is still lacking. To determine the role played by thrombin and its receptor in neointimal accumulation of smooth muscle cells in a rabbit carotid artery model, we have used an 18 mer antisense phosphorothioate oligonucleotide (ODN) directed against the translation initiation region of the human thrombin receptor gene. The antisense ODN inhibited in a dose‐dependent manner thrombin‐ or thrombin receptor activating peptide‐induced human aortic smooth muscle cell proliferation. The growth‐inhibitory effect of thrombin receptor antisense ODN was preventable by an excess of sense oligomer and specific for thrombin. The suppression of growth was accompanied by a marked decrease of the level of thrombin receptor expression as evidenced by [ 125 l]‐thrombin binding to smooth muscle cells. Under the same experimental conditions, the corresponding sense ODN was inactive. The effect of the antisense ODN on intimal smooth muscle hyperplasia in rabbit carotid arteries subjected to endothelial injury was then investigated. The topical application of the antisense (500 μg/artery) but not the sense ODN dissolved in F127 pluronic gel around the injured artery resulted, 2 weeks after the application, in a dramatic reduction of the expression of the thrombin receptor mRNA and protein levels as determined by in situ hybridization and immunohistochemistry. However, intimal smooth muscle cell accumulation as estimated by an intimal to medial cross‐sectional area ratio was reduced only by 2.7% (vs. 10.3% for the sense ODN), whereas r‐hirudin (200 μg/kg/day, sc), a potent direct thrombin inhibitor significantly reduced the formation of neointima in denuded carotid arteries (35.4% inhibition, P = 0.03). J. Cell. Physiol. 170:106–114, 1997. © 1997 Wiley‐Liss, Inc.