Chimeric DNA–RNA hammerhead ribozyme targeting transforming growth factor-β1 mRNA inhibits neointima formation in rat carotid artery after balloon injury
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- 作者：Ando ; Hideyuki ; Fukuda ; Noboru ; Kotani ; Motoko ; Yokoyama ; Shin-ichiro ; Kunimoto ; Satoshi ; Matsumoto ; Koichi ; et. al.
- 关键词：Ribozyme ; TGF-β ; 1 (targeting transforming growth factor-β ; 1) ; Smooth muscle cell ; vascular ; CTGF (connective tissue growth factor)
- 刊名：European Journal of Pharmacology
- 出版年：2004
- 出版时间：January 12, 2004
- 年：2004
- 卷：483
- 期：2-3
- 页码：207-214
- 全文大小：536 K
文摘
We designed and synthesized a chimeric DNA–RNA hammerhead ribozyme targeting transforming growth factor (TGF)-β1 mRNA and found that this ribozyme effectively and specifically inhibited growth of vascular smooth muscle cells. We examined the effects of the chimeric DNA–RNA hammerhead ribozyme targeting TGF-β1 mRNA on neointima formation and investigated the underlying mechanism to develop a possible gene therapy for coronary artery restenosis after percutaneous transluminal coronary angioplasty. Expression of mRNAs encoding TGF-β1, p27kip1, and connective tissue growth factor (CTGF) in carotid artery increased after balloon injury. Fluorescein-isothiocyanate (FITC)-labeled ribozyme was taken up into the midlayer smooth muscle of the injured carotid artery. Both 2 and 5 mg of ribozyme reduced neointima formation by 65 % compared to that of controls. Ribozyme markedly decreased expression of TGF-β1 mRNA and protein in injured vessel. Mismatch ribozyme had no effect on expression of TGF-β1 mRNA protein in injured vessel. Ribozyme markedly decreased expression of fibronectin, p27kip1, and CTGF mRNAs in injured vessel, whereas a mismatch ribozyme had no effect on these mRNAs. These findings indicate that the chimeric DNA–RNA hammerhead ribozyme targeting TGF-β1 mRNA inhibits neointima formation in rat carotid artery after balloon injury with suppression of TGF-β1 and inhibition of extracellular matrix and CTGF. In conclusion, the hammerhead ribozyme against TGF-β1 may have promise as a therapy for coronary artery restenosis after percutaneous transluminal coronary angioplasty.