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.
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.
Authors: Alfonso Eirin; Monika L Gloviczki; Hui Tang; Mario Gössl; Kyra L Jordan; John R Woollard; Amir Lerman; Joseph P Grande; Stephen C Textor; Lilach O Lerman Journal: Eur Heart J Date: 2012-07-06 Impact factor: 29.983
Authors: Li-Jun Ma; Bridgette A Corsa; Jun Zhou; HaiChun Yang; HaiJing Li; Yi-Wei Tang; Vladimir R Babaev; Amy S Major; MacRae F Linton; Sergio Fazio; Tracy E Hunley; Valentina Kon; Agnes B Fogo Journal: Am J Physiol Renal Physiol Date: 2011-03-02
Authors: Alfonso Eirin; Xin Zhang; Xiang-Yang Zhu; Hui Tang; Kyra L Jordan; Joseph P Grande; Allan B Dietz; Amir Lerman; Stephen C Textor; Lilach O Lerman Journal: Nephrol Dial Transplant Date: 2013-10-03 Impact factor: 5.992