Angiotensin II Receptor Blocker Inhibits Neointimal Hyperplasia Through Regulation of Smooth Muscle–Like Progenitor Cells

Author:

Yamada Takaaki1,Kondo Takahisa1,Numaguchi Yasushi1,Tsuzuki Michitaka1,Matsubara Tatsuaki1,Manabe Ichiro1,Sata Masataka1,Nagai Ryozo1,Murohara Toyoaki1

Affiliation:

1. From the Department of Cardiology (T.Y., T.K., Y.N., M.T., T. Matsubara, T. Murohara), Nagoya University Graduate School of Medicine, and the Department of Cardiology, Faculty of Medicine (I.M., M.S., R.N.), University of Tokyo, Japan.

Abstract

Objectives— Angiotensin II (ATII) type 1 receptor (AT1R) blocker (ARB) has been shown to inhibit neointimal formation. Bone marrow–derived mononuclear cells (BM-MNCs) give rise to smooth muscle (SM)-like cells at injured arterial wall and contribute to neointimal formation. However, role of the renin—angiotensin system in the homing process of SM-like cells during neointimal formation is unknown. Material and Methods— When human BM-MNCs and peripheral blood MNCs (PB-MNCs) were cultured under treatment with PDGF-BB and bFGF, these cells gave rise to SM-like cells with expression of αSMA, SMemb, and SM1 proteins. RT-PCR showed the expression of AT1R, ATII type 2 receptor (AT2R), αSMA, and SMemb mRNAs. ATII accelerated the differentiation of SM-like cells, which was inhibited by an ARB CV11974 ( P <0.05). We then examined the effects of ATII, CV11974, and AT2R antagonist PD123319 on neointimal formation and BM-derived SM-like cell incorporation at injured arteries in vivo. BM from green fluorescence protein (GFP)-transgenic mice was transplanted to irradiated WT mice. GFP-BM chimera mice were subjected to wire injury on the left femoral artery. ATII (100 ng/kg/min) stimulated whereas CV11974 (1 mg/kg/d) inhibited neointimal formation. Number of GFP + αSMA + cells at neointima correlated with the intima/media ratio ( r =0.69, P <0.05). Conclusion— BM-derived SM-like progenitor cells contributed to the neointimal formation after arterial injury. ATII accelerated whereas ARB suppressed this process. These are new aspects of the ARB-mediated inhibition of atherosclerotic disease progression.

Publisher

Ovid Technologies (Wolters Kluwer Health)

Subject

Cardiology and Cardiovascular Medicine

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