Published Online
on August 28, 2006

A more recent version of this article appeared on October 1, 2006

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Submitted on May 1, 2006
Revised on June 2, 2006

Angiotensin II Type 1 Receptor Blockade Attenuates In-Stent Restenosis by Inhibiting Inflammation and Progenitor Cells

Kisho Ohtani; Kensuke Egashira^*; Yoshiko Ihara; Kaku Nakano; Kouta Funakoshi; Gang Zhao; Masataka Sata; and Kenji Sunagawa

From the Department of Cardiovascular Medicine (K.O., K.E., G.Z., Y.I., K.F., K.N., K.S.), Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan; and the Department of Cardiovascular Medicine (M.S.), Graduate School of Medical Sciences, University of Tokyo, Tokyo, Japan.

^* To whom correspondence should be addressed. E-mail: egashira{at}cardiol.med.kyushu-u.ac.jp.

Abstract--The precise mechanism by which angiotensin II type 1 receptor blocker reduces in-stent restenosis in clinical trials is unclear. We, therefore, investigated the mechanism of in-stent neointima formation. Male cynomolgus monkeys and rabbits were fed a high-cholesterol diet and were allocated to untreated control and type 1 receptor blocker groups. Five days after grouping, multilink stents were implanted in the iliac artery. The type 1 receptor blocker reduced the development of in-stent neointima formation by 30% in rabbits and monkeys. To investigate potential mechanisms, we examined the expression of renin-angiotensin system markers, all of which increased in monocytes and smooth muscle-like cells in the neointima and media within 7 days. The type 1 receptor blocker attenuated increased oxidative stress, the enhanced expression of markers of the rennin-angiotensin system and monocyte chemoattractant protein-1, and macrophage infiltration. The effects of type 1 receptor blocker on the differentiation of peripheral blood mononuclear cells into vascular progenitor cells were also examined. Treatment with type 1 receptor blocker suppressed the enhanced differentiation to smooth muscle progenitor cells induced by stenting. The type 1 receptor blocker attenuated in-stent neointima formation by inhibiting redox-sensitive inflammatory changes and by reducing recruitment of the progenitor cells. These potential actions of type 1 receptor blocker on inflammation and progenitor cells constitute a novel mechanism of suppression of in-stent restenosis by type 1 receptor blocker.

Key words: angiotensin II • oxidative stress • monocytes

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