Effect of methylene methylimino linkage of antisense oligonucleotide to the platelet-derived growth factor A-chain on growth of vascular smooth muscle cells from spontaneously hypertensive rats

Spontaneously hypertensive rats (SHR)-derived vascular smooth muscle cells show exaggerated growth and increased expression of platelet-derived growth factor (PDGF) A-chain mRNA. We examined the effect of methylene methylimin o linkage of antisense oligodeoxynucleotide, a novel modification of antise nse oligodeoxynucleotide designed to increase nuclease resistance, to PDGF A-chain on the exaggerated growth of vascular smooth muscle cells from SHR. Methylene methylimino-linked oligodeoxynucleotide provided complete resist ance against S1 nuclease. Methylene methylimino linkage of antisense oligod eoxynucleotide to PDGF A-chain resulted in a rapid inhibition of basal DNA synthesis of vascular smooth muscle cells from SHR. This inhibition was muc h greater than that produced by phosphorothioate linkage of antisense oligo deoxynucleotide to PDGF A-chain. The methylene methylimino linkage of antis ense oligodeoxynucleotide to PDGF A-chain may prove useful in the treatment of arterial proliferative diseases including hypertension. (C) 2000 Elsevi er Science B.V. All rights reserved.