Local adenoviral-mediated expression of recombinant hirudin reduces neointima formation after arterial injury.
Catalytically active thrombin, acting locally, is thought to mediate neointima formation after arterial injury. We constructed an adenovirus vector, AdHV-1.2, containing a complementary DNA for the thrombin inhibitor hirudin. AdHV-1.2 directed the synthesis and secretion of biologically active hirudin from vascular cells in vitro. In vivo gene transfer of hirudin into smooth muscle cells of injured rat carotid arteries resulted in peak secretion of at least 34+/-23 pg hirudin per vessel per 24 hours, and resulted in a significant (P<0.05) 35% reduction in neointima formation. Systemic partial thromboplastin times were not affected by local hirudin expression. These results support the hypothesis that local thrombin activity contributes to neointima formation after arterial injury and suggest that local delivery of a highly specific antithrombin may constitute an effective intervention for arterial proliferative disease.
Rade
J J
JJ
Molecular Hematology Branch, National Heart, Lung, and Blood Institute, Bethesda, Maryland 20892, USA.
Schulick
A H
AH
Virmani
R
R
Dichek
D A
DA
D000256:Adenoviridae / Q000235:genetics*; D000818:Animals; D001483:Base Sequence; D020212:Carotid Artery Injuries; D018076:DNA, Complementary / Q000235:genetics; D015870:Gene Expression; D018014:Gene Transfer Techniques; D005822:Genetic Vectors; D006629:Hirudins / Q000235:genetics* / Q000378:metabolism; D066298:In Vitro Techniques; D008297:Male; D008969:Molecular Sequence Data; D009131:Muscle, Smooth, Vascular / Q000378:metabolism; D009389:Neovascularization, Pathologic / Q000517:prevention & control*; D051381:Rats; D017207:Rats, Sprague-Dawley; D011994:Recombinant Proteins / Q000235:genetics
D018076:DNA, Complementary; D006629:Hirudins; D011994:Recombinant Proteins