(Circulation. 1996;93:10-17.)
© 1996 American Heart Association, Inc.
Articles |
Prevention of Arterial Thrombosis by Adenovirus-Mediated Transfer of Cyclooxygenase Gene
From The University of Texas–Houston Health Science Center (P.Z., J.M., X.-M.X., D.L.-M., L.M.B., J.T.W., K.K.W.); University of Texas Southwestern Medical School, Dallas (R.S.M.); and Texas Heart Institute, Houston, Tex (F.J.C., L.M.B., J.T.W.).
Correspondence to Kenneth K. Wu, MD, Professor and Director, Division of Hematology, and Vascular Biology Research Center, Department of Medicine, University of Texas–Houston Medical School, 6431 Fannin, MSB 5.016, Houston, TX 77030.
Background Prostacyclin is an important vasoprotective molecule. It inhibits platelet aggregation, monocyte interaction with endothelium, and smooth muscle cell lipid accumulation. Vascular cyclooxygenase-1 (COX-1) is the rate-limiting step in prostacyclin synthesis. The objective of this study was to determine whether adenovirus-mediated transfer of COX-1 could restore COX-1 activity, augment prostacyclin synthesis, and prevent thrombus formation in a porcine carotid angioplasty model.
Methods and Results Human COX-1 cDNA driven by a
cytomegalovirus promoter was constructed into a
replication-defective adenovirus 5 vector by homologous
recombination. Recombinant adenovirus without a foreign gene (Ad-RR)
and buffer were included as controls. Recombinant Ad-LacZ was used for
marking the transfected cells in vivo. In the in vitro experiments,
cultured human endothelial cells (ECs) and porcine
arterial smooth muscle cells (SMCs) were incubated with
Ad-COX-1 for 2 hours and 6-keto-PGF1
level and the
transgene expression were determined 72 hours after infection. In the
in vivo experiments, recombinant adenoviruses were directly instilled
into angioplasty-injured porcine carotid arteries for 30 minutes.
Cyclic flow changes were monitored for 10 days and thrombus formation
was examined histologically thereafter. Transgene
expression and prostaglandin I2
(PGI2) synthesis by the injured arteries were determined.
Cultured ECs infected with Ad-COX-1 produced a fivefold to eightfold
increase in PGI2, and the transgene expression in
cultured porcine SMCs was demonstrated by Northern analysis.
Direct administration of Ad-COX-1 at a dose of 3x1010 pfu
completely inhibited carotid cyclic flow changes and thrombus formation
accompanied by a fourfold increase in PGI2 synthesis by the
injured arteries 10 days after infection, whereas Ad-COX-1 at a lower
dose, 5x109 pfu, had no antithrombotic effects when
compared with Ad-RR vector and buffer controls.
Conclusions Adenovirus-mediated transfer of COX-1 to angioplasty-injured carotid arteries was efficacious in augmenting PGI2 synthesis and was associated with an inhibition of thrombosis when a relatively high titer of adenovirus was instilled.
Key Words: thrombosis • prostaglandins • gene transfer • angioplasty
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