A Novel alphavbeta3 integrin antagonist suppresses neointima formation for more than 4 weeks after balloon injury in rats.
OBJECTIVE
We performed a detailed kinetic analysis in a rat balloon injury model to clarify the essential roles of alphavbeta3 integrin and endothelial cell (EC) regeneration in neointima formation. Using this model, we evaluated the antistenotic effect of Dainippon compound BS-1417, a novel alphavbeta3 integrin antagonist.


RESULTS
Kinetic analysis using RT-PCR showed that alphavbeta3 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.


CONCLUSIONS
We clarified that alphavbeta3 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.
Honda
Yayoi
Y
Pharmacology and Microbiology Research Laboratories, Dainippon Pharmaceutical Co., Ltd., Suita, Osaka, Japan. yayoi-honda@dainippon-pharm.co.jp
Kitano
Tomoko
T
Fukuya
Fumiyo
F
Sato
Yuji
Y
Iwama
Seiji
S
Morie
Toshiya
T
Notake
Mitsue
M
D000800:Angioplasty, Balloon / Q000009:adverse effects*; D000818:Animals; D002339:Carotid Arteries / Q000187:drug effects / Q000473:pathology / Q000502:physiology; D020212:Carotid Artery Injuries / Q000188:drug therapy* / Q000473:pathology*; D016893:Carotid Stenosis / Q000473:pathology / Q000628:therapy*; D004730:Endothelium, Vascular / Q000187:drug effects / Q000473:pathology / Q000502:physiology; D015870:Gene Expression / Q000187:drug effects; D039302:Integrin alphaVbeta3 / Q000037:antagonists & inhibitors* / Q000235:genetics; D008297:Male; D010879:Piperazines / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012038:Regeneration / Q000187:drug effects; D013997:Time Factors; D017539:Tunica Intima / Q000187:drug effects / Q000473:pathology / Q000502:physiology; D015854:Up-Regulation / Q000187:drug effects
C539746:BS 1417; D039302:Integrin alphaVbeta3; D010879:Piperazines