BACKGROUND: We sought to determine the efficacy and specificity of a new c-myb antisense by inhibiting neointimal hyperplasia in a rat abdominal aorta injury model. Using c-myb antisense oligonucleotides, inhibition of vascular smooth muscle cell proliferation has been reported. METHODS: Sixty-six male Wistar rats had a de-endothelialization of the abdominal aorta. Following a double blind randomization protocol, F127 pluronic gel containing one of the five oligonucleotides or plain gel was applied around the aorta: 1) 18-mer c-myb antisense (AS18) with four contiguous guanosines (G-quartet); 2) 15-mer c-myb antisense (AS15) without G-quartet; 3) 1-bp mismatch AS15 without G-quartet (MM1); 4) an oligonucleotide with G-quartet (4G), whereas the other bases were chosen at random; 5) 1-bp mismatch 4G without G-quartet (MM2). After 21 days all rats were sacrificed and aortas harvested for histomorphometric evaluation. Four rats were given fluorescent-labeled oligonucleotides to study in vivo localization after local advential delivery. RESULTS: Morphometric analysis showed significant suppression of neointimal hyperplasia in AS18 and 4G and MM2 groups compared with GEL, AS15 and MM1 groups (p<0.05). The oligonucleotide-labeled aortas showed penetration of the oligonucleotides into the media which increased with time. CONCLUSIONS: Our findings pointed to the potential non specificity of the c-myb antisense oligonucleotide in vivo. Such results will minimize the importance of antisense strategy as a potential therapeutic for preventing neointimal hyperplasia. The two oligonucleotides with a G-quartet inhibited neointimal hyperplasia in our model. Exploring a non-antisense mechanism, G-quartet oligonucleotides as potential drugs to reduce neointimal hyperplasia is attractive.
BACKGROUND: We sought to determine the efficacy and specificity of a new c-myb antisense by inhibiting neointimal hyperplasia in a ratabdominal aorta injury model. Using c-myb antisense oligonucleotides, inhibition of vascular smooth muscle cell proliferation has been reported. METHODS: Sixty-six male Wistar rats had a de-endothelialization of the abdominal aorta. Following a double blind randomization protocol, F127 pluronic gel containing one of the five oligonucleotides or plain gel was applied around the aorta: 1) 18-mer c-myb antisense (AS18) with four contiguous guanosines (G-quartet); 2) 15-mer c-myb antisense (AS15) without G-quartet; 3) 1-bp mismatch AS15 without G-quartet (MM1); 4) an oligonucleotide with G-quartet (4G), whereas the other bases were chosen at random; 5) 1-bp mismatch 4G without G-quartet (MM2). After 21 days all rats were sacrificed and aortas harvested for histomorphometric evaluation. Four rats were given fluorescent-labeled oligonucleotides to study in vivo localization after local advential delivery. RESULTS: Morphometric analysis showed significant suppression of neointimal hyperplasia in AS18 and 4G and MM2 groups compared with GEL, AS15 and MM1 groups (p<0.05). The oligonucleotide-labeled aortas showed penetration of the oligonucleotides into the media which increased with time. CONCLUSIONS: Our findings pointed to the potential non specificity of the c-myb antisense oligonucleotide in vivo. Such results will minimize the importance of antisense strategy as a potential therapeutic for preventing neointimal hyperplasia. The two oligonucleotides with a G-quartet inhibited neointimal hyperplasia in our model. Exploring a non-antisense mechanism, G-quartet oligonucleotides as potential drugs to reduce neointimal hyperplasia is attractive.