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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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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Decreased Ang II–induced abdominal aortic aneurysm formation and MMP-2 a...
Decreased Ang II–induced abdominal aortic aneurysm formation and MMP-2 and MMP-9 activity in ApoE–/–OPN–/– mice. (a) Representative aorta from ApoE–/–OPN+/+ and ApoE–/–OPN–/– mice infused with Ang II for 4 weeks. The arrow indicates a typical abdominal aortic aneurysm in ApoE–/–OPN+/+ mice. (b) Characteristics of aneurysmal tissue from the abdominal aorta of ApoE–/–OPN+/+ and ApoE–/–OPN–/– mice infused with Ang II. EVG staining of the elastic lamina (black) of ApoE–/–OPN+/+ (upper left) and ApoE–/–OPN–/– (upper right) mice (both ×20 magnification). The arrows indicate the disruption of the media and breaks of the elastic lamina. EVG (lower left) and trichrome (lower right) staining at higher power demonstrate the abdominal aortic wall of ApoE–/–OPN+/+ mice containing smooth muscle cells (red) between elastic fibers (black) at the edge of the disrupted media. (c) Representative zymography analysis of MMP activities in the aorta from Ang II–infused ApoE–/–OPN+/+ and ApoE–/–OPN–/– mice. Recombinant mouse MMP-2 and MMP-9 was activated by incubation with p-aminophenylmercuric acetate and used for calibration. (d) Representative Western blot analysis of aortic MMP-2 expression in ApoE–/–OPN+/+ and ApoE–/–OPN–/– mice. Recombinant MMP-2 and MMP-9 was used as positive control and for determination of specificity.