Adenovirus-Encoded Hammerhead Ribozyme to PDGF A-Chain mRNA Inhibits Neointima Formation after Arterial Injury

Abstract

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 (10⁸ 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.