Adenovirus-encoded hammerhead ribozyme to PDGF A-chain mRNA inhibits neointima formation after arterial injury.
To develop a strategy for gene therapy of restenosis following coronary angioplasty, we examined the effects of a recombinant adenovirus vector encoding a hammerhead ribozyme specific for rat platelet-derived growth factor (PDGF) A-chain mRNA (Ad. Ribozyme) and a control recombinant adenovirus vector encoding the Escherichia coli LacZ gene (Ad.LacZ) on neointima formation in rat carotid artery after balloon injury. Ad. Ribozyme (10(8) PFU/ml) markedly reduced the increased expression of PDGF A-chain mRNA and protein. Ad. Ribozyme significantly decreased the intima/media ratio (68%) of the injured artery, whereas Ad.LacZ had no effect on the intima/media ratio. Most carotid arteries developed thrombi by 14 days after balloon injury, whereas Ad. Ribozyme completely inhibited thrombus formation. Expression of thromboxane A2 (TXA2) receptor mRNA was significantly increased after balloon injury. Ad. Ribozyme significantly decreased the levels of TXA2 receptor. Expression of prostaglandin I2 (PGI2) synthase mRNA was significantly decreased after balloon injury. Ad. Ribozyme significantly increased levels of PGI2 synthase mRNA after balloon injury. The observation that adenovirus-encoded ribozyme to PDGF A-chain inhibits neointima formation may serve as a novel strategy to prevent restenosis after coronary angioplasty. Inhibition of growth factors by genetic approaches may yield new insights into the mechanisms underlying responses to vascular injury and lead to new therapeutic applications.
Lin
Zhi-Hong
ZH
Second Department of Internal Medicine, Nihon University School of Medicine, Tokyo, Japan.
Fukuda
Noboru
N
Suzuki
Ryo
R
Takagi
Hiroto
H
Ikeda
Yukihiro
Y
Saito
Satoshi
S
Matsumoto
Koichi
K
Kanmatsuse
Katsuo
K
Mugishima
Hideo
H
D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D002339:Carotid Arteries / Q000187:drug effects / Q000378:metabolism*; D002340:Carotid Artery Diseases / Q000517:prevention & control; D020212:Carotid Artery Injuries / Q000150:complications*; D002404:Catheterization; D011464:Epoprostenol / Q000235:genetics; D018014:Gene Transfer Techniques; D005822:Genetic Vectors; D008297:Male; D009389:Neovascularization, Pathologic / Q000517:prevention & control*; D010982:Platelet-Derived Growth Factor / Q000037:antagonists & inhibitors* / Q000235:genetics; D016337:RNA, Catalytic / Q000235:genetics / Q000494:pharmacology*; D012333:RNA, Messenger / Q000037:antagonists & inhibitors / Q000187:drug effects; D051381:Rats; D017208:Rats, Wistar; D044244:Receptors, Thromboxane A2, Prostaglandin H2 / Q000235:genetics; D013927:Thrombosis / Q000517:prevention & control; D017539:Tunica Intima / Q000187:drug effects*; D014949:Wounds, Nonpenetrating / Q000150:complications
D010982:Platelet-Derived Growth Factor; D016337:RNA, Catalytic; D012333:RNA, Messenger; D044244:Receptors, Thromboxane A2, Prostaglandin H2; C427204:hammerhead ribozyme; C075278:platelet-derived growth factor A; D011464:Epoprostenol