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. CONCLUSIONS: 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.
BACKGROUND: We previously demonstrated that vascular injury-induced neointima formation is exaggerated in humanC-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 humanCRP 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, humanCRP elicited increased expression of C3 by bone marrow-derived macrophages. CONCLUSIONS:HumanCRP 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 humanCRP prevents CRP-driven exacerbation of the injury response. In the CRPtg model system, mouseC3 is essential for the effect of humanCRP.
Authors: Hwee Teoh; Adrian Quan; Fina Lovren; Guilin Wang; Sam Tirgari; Paul E Szmitko; Alexander J Szalai; Michael E Ward; Subodh Verma Journal: Atherosclerosis Date: 2008-03-20 Impact factor: 5.162
Authors: Paul Elliott; John C Chambers; Weihua Zhang; Robert Clarke; Jemma C Hopewell; John F Peden; Jeanette Erdmann; Peter Braund; James C Engert; Derrick Bennett; Lachlan Coin; Deborah Ashby; Ioanna Tzoulaki; Ian J Brown; Shahrul Mt-Isa; Mark I McCarthy; Leena Peltonen; Nelson B Freimer; Martin Farrall; Aimo Ruokonen; Anders Hamsten; Noha Lim; Philippe Froguel; Dawn M Waterworth; Peter Vollenweider; Gerard Waeber; Marjo-Riitta Jarvelin; Vincent Mooser; James Scott; Alistair S Hall; Heribert Schunkert; Sonia S Anand; Rory Collins; Nilesh J Samani; Hugh Watkins; Jaspal S Kooner Journal: JAMA Date: 2009-07-01 Impact factor: 56.272
Authors: Kurt A Zimmerman; Dongqi Xing; Manuel A Pallero; Ailing Lu; Masahito Ikawa; Leland Black; Kenneth L Hoyt; Janusz H Kabarowski; Marek Michalak; Joanne E Murphy-Ullrich Journal: J Vasc Res Date: 2016-02-25 Impact factor: 1.934