Effect of TGF-beta(1) antisense S-oligonucleotide on synthesis and accumulation of matrix proteoglycans in balloon catheter-injured neointima of rabbit carotid arteries

Arterial matrix proteoglycans (PG) are necessary for the maintenance of vis coelastic properties of the vessel wall, but excess levels, particularly of versican and biglycan in primary and restenotic intimal thickenings, are c orrelated with increased tissue volume and with atherogenicity. There is go od evidence that the primary stimulus to increased PG synthesis, including versican and biglycan, is transforming growth factor-beta(1) (TGF-beta(1)). The aim of this study was to determine the effects of reducing endogenous TGF-beta(1) on rates and patterns of PG synthesis and on versican, biglycan and decorin accumulation in vivo. Rabbit common carotid arteries subjected to balloon catheter injury were treated with a TGF-beta(1) antisense phosp horothioate oligonucleotide applied in a pluronic gel to the adventitia. Co ntrol animals received a nonsense oligonucleotide or gel alone. TGF-beta(1) antisense (1) significantly (p < 0.005) inhibited, at day 2, the balloon c atheter-induced increase in TGF-beta(1) mRNA relative to beta-actin mRNA; ( 2) inhibited intimal thickening at 23 days by similar to 40% (p < 0.05); (3 ) inhibited (p < 0.05) PG synthesis, measured by autoradiographic detection of [H-3]glucosamine, in the media of day 2 ballooned carotids and in the s ubendothelial zone of day 23 neointima, and (4) decreased immunostaining in tensity for versican (p < 0.03) and TGF-beta(1) (p < 0.001) in the neointim a. Biglycan was reduced to a lesser extent but not significantly and decori n was not affected. Proliferating cell nuclear antigen indices were variabl e and not significantly changed. These findings confirm a role for TGF-beta (1) in developing neointima and demonstrate a specific effect on the synthe sis, distribution, and accumulation of matrix PG, particularly versican. Co pyright (C) 2000 S. Karger AG, Basel.