Effect of Phosphorothioated Oligonucleotides on Neointima Formation in the Rat Carotid Artery: Dissecting the Mechanism of Action

• Published in: Arteriosclerosis, thrombosis, and vascular biology Vol. 17; no. 11; pp. 2326 - 2332
• Main Authors: Bennett, M.R, Lindner, V, DeBlois, D, Reidy, NA, Schwartz, NA
• Format: Journal Article
• Language: English
• Published: Philadelphia, PA American Heart Association, Inc 01-11-1997; Hagerstown, MD Lippincott
• Subjects: Angioplasty, Balloon - adverse effects; Animals; Biological and medical sciences; Carotid Arteries - drug effects; Carotid Arteries - ultrastructure; Carotid Artery Injuries; Cell Count; Cell Division - drug effects; Diseases of the cardiovascular system; DNA Replication - drug effects; Gene Expression Regulation - drug effects; Genes, myc; Male; Medical sciences; Muscle, Smooth, Vascular - injuries; Muscle, Smooth, Vascular - metabolism; Muscle, Smooth, Vascular - ultrastructure; Oligonucleotides, Antisense - pharmacology; Osteopontin; Proto-Oncogene Proteins c-myc - biosynthesis; Radiotherapy. Instrumental treatment. Physiotherapy. Reeducation. Rehabilitation, orthophony, crenotherapy. Diet therapy and various other treatments (general aspects); Rats; Rats, Sprague-Dawley; RNA, Messenger - biosynthesis; Sialoglycoproteins - biosynthesis; Sialoglycoproteins - genetics; Thionucleotides - pharmacology; Tropoelastin - biosynthesis; Tropoelastin - genetics; Tunica Intima - drug effects; Tunica Intima - injuries; Wound Healing - drug effects; Cell proliferation; Endothelial cell; Rat; Rodentia; Instrumentation therapy; Instrumental dilatation; Antisense oligonucleotide; Prevention; Restenosis; Pathology; Vertebrata; Optical microscopy; Mammalia; Treatment; Animal; Carotid; Complication; Mechanism of action
• ISSN: 1079-5642; 1524-4636
• DOI: 10.1161/01.ATV.17.11.2326

Several studies have shown that single-dose administration of agents that inhibit medial cell replication, such as antisense oligonucleotides to cell replication genes, can inhibit neointima formation after arterial injury. However, the precise mechanism of action of these agents is unknown. We analyzed the effect of phosphorothioated oligonucleotides delivered periadventitially on the response to injury in the balloon-injured rat carotid artery. Antisense oligonucleotides to c-myc suppressed medial replication 2 days after injury, but this effect was not present at 4 or 14 days. Endothelial cell proliferation was not affected by antisense oligonucleotides. There was, however, a significant suppression of intimal area and intima/media ratio at 14 days and an increase in lumen area in the antisense-treated group. Indeed, an increase in the number of medial cells at 14 days in the antisense group indicated that most of the effect of the agent was due to the suppression of cell migration. No effect was noted on expression of two genes, osteopontin and tropoelastin, used as markers of modulation of smooth muscle cells to a "neonatal" phenotype at 4 days after injury. Because no effect on cell proliferation could be demonstrated after 2 days, our data indicate that an early effect of the antisense agent mediates its longer-term effects. We suggest that this effect may be due to the suppression of migration of medial smooth muscle cells rather than the suppression of medial or intimal cell proliferation. (Arterioscler Thromb Vasc Biol. 1997;17:2326-2332.)