LOCAL ADENOVIRAL-MEDIATED EXPRESSION OF RECOMBINANT HIRUDIN REDUCES NEOINTIMA FORMATION AFTER ARTERIAL INJURY

Catalytically active thrombin, acting locally, is thought to mediate n eointima formation after arterial injury. We constructed an adenovirus vector, AdHV-1.2, containing a complementary DNA for the thrombin inh ibitor hirudin. AdHV-1.2 directed the synthesis and secretion of biolo gically active hirudin from vascular cells in vitro. In vivo gene tran sfer of hirudin into smooth muscle cells of injured rat carotid arteri es resulted in peak secretion of at least 34 +/- 23 pg hirudin per ves sel per 24 hours, and resulted in a significant (P < 0.05) 35% reducti on in neointima formation. Systemic partial thromboplastin times were not affected by local hirudin expression. These results support the hy pothesis that local thrombin activity contributes to neointima formati on after arterial injury and suggest that local delivery of a highly s pecific antithrombin may constitute an effective intervention for arte rial proliferative disease.