on September 16, 2004
Published online before print September 16, 2004, doi: 10.1161/01.ATV.0000145607.03879.e0
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Submitted on May 28, 2004
Accepted on September 1, 2004
Angiotensin II Amplifies Macrophage-Driven Atherosclerosis
Ayabe Nobuhiko ;
From the Departments of Pediatrics and Medicine and Pathology, Vanderbilt University School of Medicine, Nashville, Tenn.
* To whom correspondence should be addressed. 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. Animal did not differ in body weight, blood pressure, cholesterol/triglycerides, or peripheral blood monocyte count. 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.
Conclusion--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.
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