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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2004;24:2143.)
© 2004 American Heart Association, Inc.

Atherosclerosis and Lipoproteins

Angiotensin II Amplifies Macrophage-Driven Atherosclerosis

Ayabe Nobuhiko; Eisuke Suganuma; Vladimir R. Babaev; Agnes Fogo; Larry L. Swift; MacRae F. Linton; Sergio Fazio; Iekuni Ichikawa; Valentina Kon

From the Departments of Pediatrics and Medicine and Pathology, Vanderbilt University School of Medicine, Nashville, Tenn.

Correspondence to Valentina Kon, MD, Vanderbilt University Medical Center, Nashville, TN 37232-2584. E-mail valentina.kon{at}vanderbilt.edu

Objective— We evaluated the role of angiotensin II (AII) in a marrow-derived macrophage-driven model of atherosclerosis.

Methods and Results— Eight-week-old C57BL/6 wild-type mice were reconstituted with bone marrow harvested from apolipoprotein E-deficient (apoE–/– apoE+/+) or wild-type for apoE gene (apoE+/+ apoE+/+) mice. At 20 weeks, mice were exposed to either AII (1000 ng/kg per minute subcutaneously) or saline for 2 weeks. Animals did not differ in body weight, blood pressure, cholesterol/triglycerides, or peripheral blood monocyte counts. ApoE–/– apoE+/+ mice exposed to AII had 3-fold greater atherosclerotic area than saline-treated apoE–/– apoE+/+ mice. By contrast, AII did not affect atherosclerosis in apoE+/+ apoE+/+ mice. Macrophage-positive areas were increased by AII in mice reconstituted with either apoE-deficient or apoE-competent marrow. AII also significantly increased fragmentation of elastin laminae in both apoE–/– apoE+/+ and apoE+/+ apoE+/+ mice. In vitro, AII caused greater increase in monocyte chemoattractant protein-1–stimulated migration of macrophages harvested from AII-infused versus saline-infused mice.

Conclusions— The current studies reveal that AII has both initiating and sustaining proatherogenic effects. By promoting macrophage migration into the vascular intima, AII is pivotal in initiating atherosclerosis; by promoting elastin breaks, a novel mechanism implicated in migration and proliferation of smooth muscle cells, AII may be pivotal in subsequent development and expansion of atherosclerotic lesion.

Wild-type mice reconstituted with bone marrow from apolipoprotein E-deficient mice (apoE–/– apoE+/+) exposed to angiotensin II (AII) had 3-times greater atherosclerosis than mice reconstituted with wild-type marrow (apoE+/+ apoE+/+). AII increased macrophage-positive areas and elastin fragmentation in both groups. AII promotes macrophage migration to initiate atherosclerosis and elastin breaks that expands atherosclerosis.

Key Words: atherosclerosis • angiotensin II • macrophage

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