© 1999 American Heart Association, Inc.
Original Contribution |
Adenovirus-Mediated Local Expression of Human Tissue Factor Pathway Inhibitor Eliminates Shear Stress–Induced Recurrent Thrombosis in the Injured Carotid Artery of the Rabbit
From the Divisions of Cardiovascular Surgery (T.N., H.Y.) and Cardiology (H.U., N.A., R.K., A.T.), Research Institute of Angiocardiology, Faculty of Medicine, Kyushu University, Fukuoka; First Department of Pathology, Miyazaki Medical College (Y.A.), Miyazaki; and The Chemo-Sero-Therapeutic Research (Y.N., Y.K.), Kumamoto, Japan.
Correspondence to Hikaru Ueno, MD, PhD, Associate Professor of Medicine, Department of Cardiology, Kyushu University School of Medicine, Fukuoka, 812-8582, Japan. E-mail ueno{at}med.kyushu-u.ac.jp
Abstract—The main cause of acute coronary syndrome may be recurrent thrombosis, which is initiated by the activation of the extrinsic coagulation pathway. Tissue factor (TF) pathway inhibitor (TFPI) efficiently inhibits an early step in this pathway by the formation of a complex with factor VIIa, TF, and factor Xa. We determined whether local TFPI gene transfer can inhibit thrombosis in an injured artery without inducing systemic side effects. Balloon-injured rabbit carotid arteries were infected with an adenoviral vector that expressed either human TFPI (AdCATFPI) or bacterial ß-galactosidase (AdCALacZ). Two to 6 days after gene transfer, thrombosis was induced by the production of constant stenosis of the artery, and blood flow was measured continuously with an electromagnetic flow probe. A cyclic flow variation, which is thought to reflect the recurrent formation and dislodgment of mural thrombi, was observed in all AdCALacZ-infected arteries as well as in saline-infused arteries. In contrast, no cyclic flow variation was detectable in AdCATFPI-transfected arteries, even in the presence of epinephrine (1 µg · kg-1 · min-1 infusion). Prothrombin time, activated partial thromboplastin time, and the ex vivo platelet aggregation induced by either adenosine diphosphate or collagen were unaltered in AdCATFPI-infected rabbits. We found that in vivo TFPI gene transfer into an injured artery completely inhibits the recurrent thrombosis induced by shear stress even in the presence of catecholamine, without affecting systemic coagulation status. Adenovirus-mediated local expression of TFPI may have the potential for the treatment of human thrombosis.
Key Words: inhibitor • thrombosis • blood flow • gene transfer • adenovirus vector
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