Angiotensin II–accelerated atherosclerosis and aneurysm formation is attenuated in osteopontin-deficient mice
Dennis Bruemmer, … , Ronald E. Law, Willa A. Hsueh
Dennis Bruemmer, … , Ronald E. Law, Willa A. Hsueh
Published November 1, 2003
Citation Information: J Clin Invest. 2003;112(9):1318-1331. https://doi.org/10.1172/JCI18141.
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Article Cardiology

Angiotensin II–accelerated atherosclerosis and aneurysm formation is attenuated in osteopontin-deficient mice

Abstract

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.

Authors

Dennis Bruemmer, Alan R. Collins, Grace Noh, Wei Wang, Mary Territo, Sarah Arias-Magallona, Michael C. Fishbein, Florian Blaschke, Ulrich Kintscher, Kristof Graf, Ronald E. Law, Willa A. Hsueh

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Ang II–accelerated atherosclerosis in male ApoE–/–OPN+/+, ApoE–/–OPN+/–,...
Ang II–accelerated atherosclerosis in male ApoE–/–OPN+/+, ApoE–/–OPN+/–, and ApoE–/–OPN–/– OPN mice. Three-month-old mice on a regular chow diet were infused with vehicle or Ang II for 4 weeks. (a) En face analysis of aortae stained with Sudan IV to visualize accumulation of subintimal lipids present in atherosclerotic lesions. (b) Mean atherosclerotic lesion areas of the thoracic aorta from ApoE–/–OPN+/+ wild-type mice (black bars), ApoE–/–OPN+/– (gray bars), and ApoE–/–OPN–/– (white bars) mice determined by computer-assisted image analysis. Data are represented as average percentage of the total surface of the thoracic aorta and expressed as mean ± SEM. *P < 0.05 vs. ApoE–/–OPN+/+ infused with Ang II.