In:
Circulation, Ovid Technologies (Wolters Kluwer Health), Vol. 102, No. 11 ( 2000-09-12), p. 1308-1314
Kurzfassung:
Background —Because the mechanisms of atherosclerosis or restenosis after angioplasty have been postulated to involve an increase in transforming growth factor (TGF)-β, a selective decrease in TGF-β may have therapeutic value. Thus, we used the ribozyme strategy to actively cleave the targeted gene to selectively inhibit TGF-β expression. Methods and Results —We constructed ribozyme oligonucleotides (ONs) targeted to the sequence of the TGF-β gene that shows 100% homology among the human, rat, and mouse species. The specificity of ribozyme against TGF-β gene was confirmed by selective inhibition of TGF-β mRNA in cultured vascular smooth muscle cells as well as balloon-injured blood vessels in vivo. Importantly, the marked decrease in TGF-β resulted in significant inhibition of neointimal formation after vascular injury in a rat carotid artery model ( P 〈 0.01), whereas DNA-based control ONs and mismatched ribozyme ONs did not have any inhibitory effect on neointimal formation. Inhibition of neointimal formation was accompanied by (1) a reduction in collagen synthesis and mRNA expression of collagen I and III and (2) a significant decrease in DNA synthesis as assessed by proliferating cell nuclear antigen staining. Moreover, we modified ribozyme ONs containing phosphorothioate DNA and RNA targeted to the TGF-β gene. Of importance, modified ribozyme ONs showed a further reduction in TGF-β expression. Conclusions —Overall, this study provides the first evidence that selective blockade of TGF-β resulted in inhibition of neointimal formation, accompanied by a reduction in collagen synthesis and DNA synthesis in a rat model. We anticipate that modification of ribozyme ON pharmacokinetics will facilitate the potential clinical utility of the ribozyme strategy.
Materialart:
Online-Ressource
ISSN:
0009-7322
,
1524-4539
DOI:
10.1161/01.CIR.102.11.1308
Sprache:
Englisch
Verlag:
Ovid Technologies (Wolters Kluwer Health)
Publikationsdatum:
2000
ZDB Id:
1466401-X
