(Circulation. 2001;103:570.)
© 2001 American Heart Association, Inc.
Basic Science Reports |
Combination of a Brief Irrigation With Tissue Factor Pathway Inhibitor (TFPI) and Adenovirus-Mediated Local TFPI Gene Transfer Additively Reduces Neointima Formation in Balloon-Injured Rabbit Carotid Arteries
From the Departments of Cardiology (N.A., A.T., H.U.) and Cardiovascular Surgery (T.N.), Graduate School of Medical Sciences, Kyushu University, Fukuoka; the Department of Pathology, Miyazaki Medical College, Miyazaki (K.M., Y.A.); and Chemo-Sero-Therapeutic Research, Kumamoto (Y.K.), Japan. Dr Ueno is now at the Department of Biochemistry and Molecular Pathophysiology, University of Occupational and Environmental Health, Kitakyushu, Japan.
Correspondence to Hikaru Ueno, MD, PhD, Professor, Department of Biochemistry and Molecular Pathophysiology, University of Occupational and Environmental Health, School of Medicine, Kitakyushu, 807-8555 Japan. E-mail hueno{at}med.uoeh-u.ac.jp
Background—Tissue factor pathway inhibitor (TFPI) is a physiological antagonist of TF. We tested whether a brief irrigation with TFPI protein (rTFPI) or TFPI gene transfer into injured arteries would suppress TF activity and reduce fibroproliferative changes and investigated whether a combination of these methods would show an additive effect.
Methods and Results—We prepared adenoviruses expressing either TFPI (AdTFPI) or bacterial ß-galactosidase (AdLacZ). Rabbit carotid arteries were balloon-injured and either infected with AdTFPI (or AdLacZ) or irrigated briefly with rTFPI (or saline). After injury, TF activity in arteries increased and was sustained; however, it was suppressed during the initial 24 hours by rTFPI irrigation (but not by gene transfer) and for a substantial period of time by TFPI gene transfer (but not by rTFPI irrigation). Four weeks later, the ratio of the intimal to medial areas was 34.3±8.7% (mean±SD, n=14) in saline-treated arteries and 33.3±4.2% in AdLacZ-infected arteries (P=NS versus saline). However, it was reduced to 25.5±8.5% in rTFPI-irrigated arteries (P<0.01 versus saline) and to 20.7±5.3% in AdTFPI-infected arteries (P<0.01 versus AdLacZ). With a combination of irrigation and gene transfer, the ratio was further reduced to 12.6±4.7% (P<0.01 versus rTFPI, P<0.05 versus AdTFPI). Systemic coagulation status was not affected in these animals.
Conclusions—A combination of rTFPI irrigation and TFPI gene transfer overcomes the shortcomings shown by each method when used alone and achieves a full coverage of TF activity suppression, thereby enhancing their therapeutic effects without systemic side effects. This combination may be an effective strategy for the prevention of thrombosis and proliferative changes after angioplasty in humans.
Key Words: anticoagulants • gene therapy • platelets • thrombin • thrombus
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