Journal
ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY
Volume 30, Issue 6, Pages 1189-U254Publisher
LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1161/ATVBAHA.110.205377
Keywords
atherosclerosis; C-reactive protein; complement; vascular biology
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Funding
- American Heart Association [0930098N, 09BGIA2250367]
- Walter B. Frommeyer, Jr, Fellowship in Investigative Medicine
- National Heart, Lung, and Blood Institute [HL07457, HL64614, HL75211, HL087980, HL080017, HL044195]
- Isis Pharmaceuticals Inc.
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Background-We previously demonstrated that vascular injury-induced neointima formation is exaggerated in human C-reactive protein (CRP) transgenic (CRPtg) compared to nontransgenic (NTG) mice. We now test the hypothesis that complement is required for this effect. Methods and Results-CRPtg and NTG with a normal complement system versus their counterparts lacking expression of complement component 3 (C3) protein (CRPtg/C3(-/-) and NTG/C3(-/-)) underwent carotid artery ligation. Twenty-eight days later, the injured vessels in CRPtg had thicker neointimas and more immunoreactive C3 in the surrounding adventitia compared with NTG. In CRPtg/C3(-/-), there was no increase in neointimal thickness compared with NTG or NTG/C3(-/-). Decreasing human CRP blood levels through administration of a selective antisense oligonucleotide eliminated the depletion of serum C3 associated with vascular injury and reduced immunoreactive C3 in the resultant lesions. In injured vessels, C3 colocalized with F4/80 (macrophage marker), and in vitro, human CRP elicited increased expression of C3 by bone marrow-derived macrophages. Conclusion-Human CRP exaggeration of neointima formation in injured mouse carotid arteries associates with decreased circulating C3 and increased tissue-localized C3. C3 elimination or pharmacological reduction of human CRP prevents CRP-driven exacerbation of the injury response. In the CRPtg model system, mouse C3 is essential for the effect of human CRP. (Arterioscler Thromb Vasc Biol. 2010; 30: 1189-1195.)
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