OBJECTIVE: To investigate whether citrullinated proteins within the atherosclerotic plaque can be targeted by anti-citrullinated protein antibodies (ACPAs), forming stimulatory immune complexes that propagate the progression of atherosclerosis. METHODS: Protein lysates prepared from atherosclerotic segments of human aorta were assessed for the presence of citrulline-modified proteins, and specifically citrullinated fibrinogen (Cit-fibrinogen), by immunoprecipitation and/or immunoblotting followed by mass spectrometry. Immunohistochemical analysis of coronary artery plaque was performed to determine the presence of citrullinated proteins and peptidylarginine deiminase type 4 (PAD-4). Serum levels of anti-cyclic citrullinated peptide (anti-CCP), anti-citrullinated vimentin (anti-Cit-vimentin), and anti-Cit-fibrinogen antibodies were measured in 134 women with seropositive rheumatoid arthritis; these subjects had previously been characterized for the presence of subclinical atherosclerosis, by electron beam computed tomography scanning. RESULTS: Western blot analysis of atherosclerotic plaque lysates demonstrated several citrullinated proteins, and the presence of Cit-fibrinogen was confirmed by immunoprecipitation and mass spectrometry. Immunohistochemical analysis showed colocalization of citrullinated proteins and PAD-4 within the coronary artery plaque. In age-adjusted regression models, antibodies targeting Cit-fibrinogen and Cit-vimentin, but not CCP-2, were associated with an increased aortic plaque burden. CONCLUSION: Citrullinated proteins are prevalent within atherosclerotic plaques, and certain ACPAs are associated with the atherosclerotic burden. These observations suggest that targeting of citrullinated epitopes, specifically Cit-fibrinogen, within atherosclerotic plaques could provide a mechanism for the accelerated atherosclerosis observed in patients with RA.
OBJECTIVE: To investigate whether citrullinated proteins within the atherosclerotic plaque can be targeted by anti-citrullinated protein antibodies (ACPAs), forming stimulatory immune complexes that propagate the progression of atherosclerosis. METHODS: Protein lysates prepared from atherosclerotic segments of human aorta were assessed for the presence of citrulline-modified proteins, and specifically citrullinated fibrinogen (Cit-fibrinogen), by immunoprecipitation and/or immunoblotting followed by mass spectrometry. Immunohistochemical analysis of coronary artery plaque was performed to determine the presence of citrullinated proteins and peptidylarginine deiminase type 4 (PAD-4). Serum levels of anti-cyclic citrullinated peptide (anti-CCP), anti-citrullinated vimentin (anti-Cit-vimentin), and anti-Cit-fibrinogen antibodies were measured in 134 women with seropositive rheumatoid arthritis; these subjects had previously been characterized for the presence of subclinical atherosclerosis, by electron beam computed tomography scanning. RESULTS: Western blot analysis of atherosclerotic plaque lysates demonstrated several citrullinated proteins, and the presence of Cit-fibrinogen was confirmed by immunoprecipitation and mass spectrometry. Immunohistochemical analysis showed colocalization of citrullinated proteins and PAD-4 within the coronary artery plaque. In age-adjusted regression models, antibodies targeting Cit-fibrinogen and Cit-vimentin, but not CCP-2, were associated with an increased aortic plaque burden. CONCLUSION: Citrullinated proteins are prevalent within atherosclerotic plaques, and certain ACPAs are associated with the atherosclerotic burden. These observations suggest that targeting of citrullinated epitopes, specifically Cit-fibrinogen, within atherosclerotic plaques could provide a mechanism for the accelerated atherosclerosis observed in patients with RA.
Authors: D Makrygiannakis; E af Klint; I E Lundberg; R Löfberg; A-K Ulfgren; L Klareskog; A I Catrina Journal: Ann Rheum Dis Date: 2006-03-15 Impact factor: 19.103
Authors: Miguel A Gonzalez-Gay; Carlos Gonzalez-Juanatey; Maria J Lopez-Diaz; Angela Piñeiro; Carlos Garcia-Porrua; Jose A Miranda-Filloy; William E R Ollier; Javier Martin; Javier Llorca Journal: Arthritis Rheum Date: 2007-02-15
Authors: Amy H Kao; Shanthi Krishnaswami; Amylynn Cunningham; Daniel Edmundowicz; Penelope A Morel; Lewis H Kuller; Mary Chester M Wasko Journal: J Rheumatol Date: 2008-01 Impact factor: 4.666
Authors: Jeremy Sokolove; Reuven Bromberg; Kevin D Deane; Lauren J Lahey; Lezlie A Derber; Piyanka E Chandra; Jess D Edison; William R Gilliland; Robert J Tibshirani; Jill M Norris; V Michael Holers; William H Robinson Journal: PLoS One Date: 2012-05-25 Impact factor: 3.240
Authors: Xiaoyan Zhao; Nwora Lance Okeke; Orr Sharpe; Franak M Batliwalla; Annette T Lee; Peggy P Ho; Beren H Tomooka; Peter K Gregersen; William H Robinson Journal: Arthritis Res Ther Date: 2008-08-18 Impact factor: 5.156
Authors: E Blair Solow; Fang Yu; Geoffrey M Thiele; Jeremy Sokolove; William H Robinson; Zachary M Pruhs; Kaleb D Michaud; Alan R Erickson; Harlan Sayles; Gail S Kerr; Angelo L Gaffo; Liron Caplan; Lisa A Davis; Grant W Cannon; Andreas M Reimold; Joshua Baker; Pascale Schwab; Daniel R Anderson; Ted R Mikuls Journal: Rheumatology (Oxford) Date: 2015-04-07 Impact factor: 7.580
Authors: Laura Geraldino-Pardilla; Jon T Giles; Jeremy Sokolove; Afshin Zartoshti; William H Robinson; Matthew Budoff; Robert Detrano; Sabahat Bokhari; Joan M Bathon Journal: Arthritis Care Res (Hoboken) Date: 2017-07-10 Impact factor: 4.794
Authors: Jason S Knight; Wei Luo; Alexander A O'Dell; Srilakshmi Yalavarthi; Wenpu Zhao; Venkataraman Subramanian; Chiao Guo; Robert C Grenn; Paul R Thompson; Daniel T Eitzman; Mariana J Kaplan Journal: Circ Res Date: 2014-01-14 Impact factor: 17.367