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 CPN 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(-/-O)PN(-/-) mice was reduced and associated with decreased MMP-2 and MMP-9 activity. These data suggest an important role for leukocytederived OPN in mediating Ang II-accelerated atherosclerosis and aneurysm formation.