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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Figure 8

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Decreased viability of OPN–/– macrophages in atherosclerotic lesions. TU...
Decreased viability of OPN–/– macrophages in atherosclerotic lesions. TUNEL staining of comparable-sized atherosclerotic lesions from Ang II–infused ApoE–/–OPN+/+ (a) and ApoE–/–OPN–/– (b) mice. Cryostat sections were prepared and stained with TUNEL (green) as described in Methods. The elastic lamina of the vessel gives a prominent background staining allowing the detection of breaks as a common feature of Ang II infusion in ApoE–/– mice. Sections were double stained with a rat anti-mouse Mac-3 mAb for the detection of macrophages (red) and DAPI (blue) to stain DNA. The overlay projection on the lower right of each picture allows the detection of colocalizing TUNEL+ macrophages (yellow). The arrow indicates typical examples of TUNEL+ macrophages. (c) The percentage of positively stained macrophages was determined by counting the number of double-stained macrophages and total macrophages of five HPFs per cross section (n = 4) from each mouse (*P < 0.05). (d) Representative Western immunoblot for aortic caspase-3 expression from ApoE–/–OPN+/+ and ApoE–/–OPN–/– mice using an Ab detecting endogenous levels of full-length caspase-3 (35 kDa) and the large fragment of caspase-3 resulting from cleavage (17 kDa).