A novel αvβ3 integrin antagonist suppresses neointima formation for more than 4 weeks after balloon injury in rats

Abstract

Objectives-We performed a detailed kinetic analysis in a rat balloon injury model to clarify the essential roles of αvβ3 integrin and endothelial cell (EC) regeneration in neointima formation. Using this model, we evaluated the antistenotic effect of Dainippon compound BS-1417, a novel αvβ3 integrin antagonist. Methods and Results-Kinetic analysis using RT-PCR showed that αvβ3 integrin-related genes are upregulated before neointima formation. Morphological and functional analyses revealed that EC regeneration requires >4 weeks after injury, and that recovery of EC normal function coincides with the arrest of neointima formation. Subcutaneous infusion of BS-1417 for 2, 4, 7, or 12 weeks after injury potently inhibited neointima formation without affecting EC regeneration. Although withdrawal of treatment with BS-1417 after short-term administration after injury resulted in catch-up growth of neointima, a long-term study suggested that this catch-up growth can be prevented by continuous administration of BS-1417 until EC regeneration. Conclusion-We clarified that αvβ3 integrin and EC regeneration play an essential role in neointima formation, and that continuous administration of BS-1417 potently and stably inhibits neointima formation without affecting EC regeneration. These findings suggest that BS-1417 might be useful as a novel systemic drug for the treatment of restenosis. © 2005 American Heart Association, Inc.