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
• Journal: The Journal of clinical investigation (J Clin Invest) Vol. 112 Issue 9 Pg. 1318-31 (Nov 2003) ISSN: 0021-9738 [Print] United States
• PMID: 14597759 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Apolipoproteins E
• Ccr2 protein, mouse
• Chemokine CCL2
• Cytokines
• RNA, Messenger
• Receptors, CCR2
• Receptors, Chemokine
• Sialoglycoproteins
• Spp1 protein, mouse
• Osteopontin
• Angiotensin II

Topics

• Angiotensin II (pharmacology)
• Animals
• Aortic Aneurysm, Abdominal (etiology, therapy)
• Apolipoproteins E (physiology)
• Arteriosclerosis (etiology, therapy)
• Cell Movement
• Cell Survival
• Chemokine CCL2 (physiology)
• Cytokines (biosynthesis)
• Gene Expression Regulation (drug effects)
• Leukocytes (physiology)
• Macrophages (physiology)
• Mice
• Mice, Inbred C57BL
• Osteopontin
• RNA, Messenger (analysis)
• Receptors, CCR2
• Receptors, Chemokine (physiology)
• Sialoglycoproteins (genetics, physiology)