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