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J Thorac Cardiovasc Surg 2004;128:357-363
© 2004 The American Association for Thoracic Surgery

Cardiopulmonary support and physiology

Locally applied cilostazol suppresses neointimal hyperplasia by inhibiting tenascin-c synthesis and smooth muscle cell proliferation in free artery grafts

^a Department of Thoracic and Cardiovascular Surgery, Tsu, Japan
^b Department of Pathology, Mie University School of Medicine, Tsu, Japan

Received for publication July 30, 2003; revisions received October 7, 2003; accepted for publication November 5, 2003.

^* Address for reprints: Koji Onoda, MD, PhD, Department of Thoracic and Cardiovascular Surgery, Mie University School of Medicine, 2-174 Edobashi, Tsu, Mie 514-8507, Japan
k-onoda{at}clin.medic.mie-u.ac.jp

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.

CONCLUSION: 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.

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