© 2006 The Japanese Biochemical Society
Regular Paper |
Novel Heparanase-Inhibiting Antibody Reduces Neointima Formation
1 Department of Biochemistry and Cell Biology, 2 Department of Chemical Engineering, and 3 Department of Bioengineering, Rice University, Houston, Texas 77005
* To whom correspondence should be addressed at: Department of Bioengineering, Rice University, 6100 Main St., P.O. Box 1892, MS-142, Houston, TX 77251, USA. Tel: +1-713-348-5955, Fax: +1-713-348-5877, E-mail: jwest{at}rice.edu
Basic fibroblast growth factor (bFGF), stored bound to heparan sulfate proteoglycans in the extracellular matrix (ECM) of the arterial media, may initiate smooth muscle cell (SMC) proliferation after coronary intervention, thus contributing to restenosis. bFGF mobilization from ECM stores after injury may be induced by platelet degranulation products such as heparanase. Therapies aimed at the inhibition of bFGF release and activation may assist in prevention of restenosis. To test this theory, we first examined the mobilization and activation of bFGF in the arterial media by platelet-derived heparanase. Heparanase, locally delivered to the rat carotid artery, was found to release bFGF and induce substantial SMC proliferation in the absence of actual vascular injury. An antibody that neutralizes heparanase was then developed and evaluated in a rat carotid balloon injury model. Local delivery of anti-heparanase IgG was found to inhibit bFGF release by approximately 60% ( p < 0·001) at 4 d; this correlated with the significant reduction in neointima formation observed at 14 d (intimal area/medial area: control 1·3 ± 0·3, anti-heparanase 0·35 ± 0·12, p < 0·0001). Platelet-derived heparanase is therefore likely to be important in initiating events leading to restenosis via bFGF mobilization. Furthermore, heparanase neutralization may assist in the prevention of restenosis following vascular injury.
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