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


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.
Nobuhiko
Ayabe
A
Department of Pediatrics, Vanderbilt University School of Medicine, Nashville, Tenn, USA.
Suganuma
Eisuke
E
Babaev
Vladimir R
VR
Fogo
Agnes
A
Swift
Larry L
LL
Linton
MacRae F
MF
Fazio
Sergio
S
Ichikawa
Iekuni
I
Kon
Valentina
V
D000804:Angiotensin II / Q000008:administration & dosage / Q000494:pharmacology*; D000818:Animals; D001057:Apolipoproteins E / Q000172:deficiency / Q000502:physiology; D001161:Arteriosclerosis / Q000378:metabolism* / Q000473:pathology*; D016026:Bone Marrow Transplantation / Q000379:methods; D002465:Cell Movement / Q000187:drug effects; D002784:Cholesterol / Q000378:metabolism; D004195:Disease Models, Animal; D005260:Female; D015918:Infusion Pumps, Implantable; D008264:Macrophages / Q000378:metabolism*; D017737:Macrophages, Peritoneal / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL
D001057:Apolipoproteins E; D000804:Angiotensin II; D002784:Cholesterol