Locally applied cilostazol suppresses neointimal hyperplasia by inhibiting tenascin-C synthesis and smooth muscle cell proliferation in free artery grafts.
OBJECTIVE
Accumulation of smooth muscle cells and extracellular matrix in the intima of artery bypass grafts induces neointimal hyperplasia, resulting in graft failure. We investigated the inhibitory effect of locally applied cilostazol, an inhibitor of cyclic adenosine monophosphate phosphodiesterase III, on neointimal hyperplasia and the role of tenascin-C synthesis and smooth muscle cell proliferation in free artery grafts. Methods and results We established a distal anastomotic stricture model of free artery graft stenosis using rat abdominal aorta. In this model, neointimal hyperplasia was observed not only in the distal anastomotic site but also in the graft body at postoperative day 14 and was markedly progressed at day 28. Strong expression of tenascin-C was found in the media and neointima of the graft body. When cilostazol was locally administered around the graft using Pluronic gel, neointimal hyperplasia of the graft was significantly suppressed in comparison with gel-treated control graft. The mean neointima/media area ratio was reduced by 86.6% for the graft body and by 75.8% for the distal anastomotic site versus the control. Cilostazol treatment decreased cell proliferation and tenascin-C expression in the neointima. In an in vitro experiment using cultured smooth muscle cells isolated from rat aorta, cilostazol completely suppressed the tenascin-C mRNA expression induced by platelet-derived growth factor-BB.


CONCLUSIONS
A single topical administration of cilostazol may suppress neointimal hyperplasia by inhibiting cell proliferation and tenascin-C synthesis in free artery grafts, presenting the potential for clinical use in vascular surgery.
Fujinaga
Kazuya
K
Department of Thoracic and Cardiovascular Surgery, Tsu, Japan.
Onoda
Koji
K
Yamamoto
Kiyohito
K
Imanaka-Yoshida
Kyoko
K
Takao
Motoshi
M
Shimono
Takatsugu
T
Shimpo
Hideto
H
Yoshida
Toshimichi
T
Yada
Isao
I
D000287:Administration, Topical; D000818:Animals; D001158:Arteries / Q000166:cytology / Q000187:drug effects*; D002455:Cell Division; D002478:Cells, Cultured; D000077407:Cilostazol; D006965:Hyperplasia; D066298:In Vitro Techniques; D008297:Male; D009130:Muscle, Smooth / Q000166:cytology / Q000187:drug effects; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology*; D051381:Rats; D011917:Rats, Inbred Lew; D019063:Tenascin / Q000037:antagonists & inhibitors* / Q000096:biosynthesis*; D013777:Tetrazoles / Q000494:pharmacology*; D017539:Tunica Intima / Q000187:drug effects* / Q000473:pathology*
D010726:Phosphodiesterase Inhibitors; D019063:Tenascin; D013777:Tetrazoles; D000077407:Cilostazol