This Article Full Text Full Text (PDF) Data Supplement All Versions of this Article: 28/1/90    most recent ATVBAHA.107.152363v1 Submit a response Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Fukuda, D. Articles by Nagai, R. Search for Related Content PubMed PubMed Citation Articles by Fukuda, D. Articles by Nagai, R.

(Arteriosclerosis, Thrombosis, and Vascular Biology. 2008;28:90.)
© 2008 American Heart Association, Inc.

Integrative Physiology/Experimental Medicine

Critical Role of Bone Marrow Angiotensin II Type 1 Receptor in the Pathogenesis of Atherosclerosis in Apolipoprotein E–Deficient Mice

Daiju Fukuda; Masataka Sata; Nobukazu Ishizaka; Ryozo Nagai

From the Departments of Cardiovascular Medicine (D.F., M.S., N.I., R.N.) and Advanced Clinical Science and Therapeutics (M.S.), University of Tokyo Graduate School of Medicine, Tokyo, Japan.

Correspondence to Dr Masataka Sata, Department of Cardiovascular Medicine, University of Tokyo Graduate School of Medicine, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan. E-mail msata-circ{at}umin.net

Abstract

Objective— It is suggested that the angiotensin II (Ang II)–Ang II type 1 receptor (AT1R) pathway plays a pivotal role in the pathogenesis of atherosclerosis. Recently, bone marrow (BM) cells were reported to express AT1R. Here, we investigated the role of AT1R in BM in the pathogenesis of atherosclerosis.

Methods and Results— Genetic ablation or pharmacological blockade of AT1R led to a significant reduction and stabilization of atherosclerotic lesions in ApoE^–/– mice. To elucidate the role of AT1R in BM, we generated several BM chimeric mice. Ang II promoted atherosclerosis progression in the BM chimeric mice that had AT1aR in BM, regardless of the absence of AT1aR in the recipient vasculature (P<0.05). BM chimeric mice whose BM AT1aR was disrupted showed significantly less atherosclerotic lesions in aorta (P<0.05) and more stable plaque with reduced accumulation of BM-derived cells compared with BM chimeric mice that had AT1aR-positive BM. Most of the BM-derived cells in atheroma were positive for a macrophage marker and expressed matrix metalloproteinase (MMP)-9 and monocyte chemoattractant protein-1.

Conclusions— Our findings suggest that AT1R in BM plays an important role in the pathogenesis of atherosclerosis.

We demonstrated potential contribution of angiotensin II type 1 receptor (AT1R) in bone marrow (BM) to the pathogenesis of atherosclerotic lesions, at least in part. Therefore, blockade of AT1R not only in vascular cells but also in BM could be an important strategy to prevent atherosclerosis.

Key Words: angiotensin II type I receptor • bone marrow • atherosclerosis • MMP-9 • MCP-1

This article has been cited by other articles:

				Y. Tsubakimoto, H. Yamada, H. Yokoi, S. Kishida, H. Takata, H. Kawahito, A. Matsui, N. Urao, Y. Nozawa, H. Hirai, et al. Bone Marrow Angiotensin AT1 Receptor Regulates Differentiation of Monocyte Lineage Progenitors From Hematopoietic Stem Cells Arterioscler Thromb Vasc Biol, October 1, 2009; 29(10): 1529 - 1536. [Abstract] [Full Text] [PDF]