Angiotensin II-accelerated atherosclerosis and aneurysm formation is attenuated in osteopontin-deficient mice.
Osteopontin (OPN) is expressed in atherosclerotic lesions, particularly in diabetic patients. To determine the role of OPN in atherogenesis, ApoE-/-OPN+/+, ApoE-/-OPN+/-, and ApoE-/-OPN-/- mice were infused with Ang II, inducing vascular OPN expression and accelerating atherosclerosis. Compared with ApoE-/-OPN+/+ mice, ApoE-/-OPN+/- and ApoE-/-OPN-/- mice developed less Ang II-accelerated atherosclerosis. ApoE-/- mice transplanted with bone marrow derived from ApoE-/-OPN-/- mice had less Ang II-induced atherosclerosis compared with animals receiving ApoE-/-OPN+/+ cells. Aortae from Ang II-infused ApoE-/-OPN-/- mice expressed less CD68, C-C-chemokine receptor 2, and VCAM-1. In response to intraperitoneal thioglycollate, recruitment of leukocytes in OPN-/- mice was impaired, and OPN-/- leukocytes exhibited decreased basal and MCP-1-directed migration. Furthermore, macrophage viability in atherosclerotic lesions from Ang II-infused ApoE-/-OPN-/- mice was decreased. Finally, Ang II-induced abdominal aortic aneurysm formation in ApoE-/-OPN-/- mice was reduced and associated with decreased MMP-2 and MMP-9 activity. These data suggest an important role for leukocyte-derived OPN in mediating Ang II-accelerated atherosclerosis and aneurysm formation.
Division of Endocrinology, Diabetes and Hypertension, David Geffen School of Medicine, University of California, Los Angeles, Warren Hall, Suite 24-130, 900 Veteran Avenue, Los Angeles, California 90095, USA. whsueh@mednet.ucla.edu
Dennis
D
Bruemmer
Alan R
AR
Collins
Grace
G
Noh
Wei
W
Wang
Mary
M
Territo
Sarah
S
Arias-Magallona
Michael C
MC
Fishbein
Florian
F
Blaschke
Ulrich
U
Kintscher
Kristof
K
Graf
Ronald E
RE
Law
Willa A
WA
Hsueh
D000804:Angiotensin II / Q000494:pharmacology*; D000818:Animals; D017544:Aortic Aneurysm, Abdominal / Q000209:etiology* / Q000628:therapy; D001057:Apolipoproteins E / Q000502:physiology; D001161:Arteriosclerosis / Q000209:etiology* / Q000628:therapy; D002465:Cell Movement; D002470:Cell Survival; D018932:Chemokine CCL2 / Q000502:physiology; D016207:Cytokines / Q000096:biosynthesis; D005786:Gene Expression Regulation / Q000187:drug effects; D007962:Leukocytes / Q000502:physiology; D008264:Macrophages / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D053495:Osteopontin; D012333:RNA, Messenger / Q000032:analysis; D054390:Receptors, CCR2; D019707:Receptors, Chemokine / Q000502:physiology; D012795:Sialoglycoproteins / Q000235:genetics / Q000502:physiology*
D001057:Apolipoproteins E; C515335:Ccr2 protein, mouse; D018932:Chemokine CCL2; D016207:Cytokines; D012333:RNA, Messenger; D054390:Receptors, CCR2; D019707:Receptors, Chemokine; D012795:Sialoglycoproteins; C506896:Spp1 protein, mouse; D053495:Osteopontin; D000804:Angiotensin II