Sequence-independent inhibition of in vitro vascular smooth muscle cell proliferation, migration, and in vivo neointimal formation by phosphorothioate oligodeoxynucleotides.
Phosphorothioate oligodeoxynucleotides (PS oligos) are antisense (sequence-specific) inhibitors of vascular smooth muscle cell (SMC) proliferation when targeted against different genes. Recently an aptameric G-quartet inhibitory effect of PS oligos has been demonstrated. To determine whether PS oligos manifest non-G-quartet, non-sequence-specific effects on human aortic SMC, we examined the effects of S-dC28, a 28-mer phosphorothioate cytidine homopolymer, on SMC proliferation induced by several SMC mitogens. S-dC28 significantly inhibited SMC proliferation induced by 10% FBS as well as the mitogens PDGF, bFGF, and EGF without cytotoxicity. Moreover, S-dC28 abrogated PDGF-induced in vitro migration in a modified micro-Boyden chamber. Furthermore, S-dC28 manifested in vivo antiproliferative effects in the rat carotid balloon injury model. S-dC28 suppressed neointimal cross-sectional area by 73% and the intima/media area ratio by 59%. Therefore, PS oligos exert potent non-G-quartet, non-sequence-specific effects on in vitro SMC proliferation and migration as well as in vivo neointimal formation.
Wang
W
W
Department of Medicine, Columbia University College of Physicians and Surgeons, New York 10032, USA.
Chen
H J
HJ
Schwartz
A
A
Cannon
P J
PJ
Stein
C A
CA
Rabbani
L E
LE
D000818:Animals; D001011:Aorta; D001483:Base Sequence; D000077214:Becaplermin; D002151:Calorimetry; D002339:Carotid Arteries / Q000187:drug effects; D020212:Carotid Artery Injuries; D002404:Catheterization / Q000009:adverse effects; D002455:Cell Division / Q000187:drug effects; D002465:Cell Movement / Q000187:drug effects; D002478:Cells, Cultured; D003907:Dexamethasone / Q000494:pharmacology; D004815:Epidermal Growth Factor / Q000494:pharmacology; D016222:Fibroblast Growth Factor 2 / Q000494:pharmacology; D006133:Growth Substances / Q000494:pharmacology*; D006801:Humans; D007770:L-Lactate Dehydrogenase; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000187:drug effects* / Q000502:physiology; D018919:Neovascularization, Physiologic / Q000187:drug effects* / Q000502:physiology; D009838:Oligodeoxyribonucleotides / Q000494:pharmacology*; D010982:Platelet-Derived Growth Factor / Q000494:pharmacology; D020574:Proto-Oncogene Proteins c-sis; D051381:Rats; D017207:Rats, Sprague-Dawley; D011994:Recombinant Proteins / Q000494:pharmacology; D013873:Thionucleotides; D017539:Tunica Intima / Q000166:cytology / Q000187:drug effects* / Q000502:physiology; D017540:Tunica Media / Q000166:cytology / Q000187:drug effects / Q000502:physiology
D006133:Growth Substances; D009838:Oligodeoxyribonucleotides; D010982:Platelet-Derived Growth Factor; D020574:Proto-Oncogene Proteins c-sis; D011994:Recombinant Proteins; D013873:Thionucleotides; D016222:Fibroblast Growth Factor 2; D000077214:Becaplermin; D004815:Epidermal Growth Factor; D003907:Dexamethasone; D007770:L-Lactate Dehydrogenase