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Supplement Article Journal of International Medical Research 2016, Vol. 44(1S) 81–84 Post-translational ! The Author(s) 2015 Reprints and permissions: modifications in rheumatoid sagepub.co.uk/journalsPermissions.nav DOI: 10.1177/0300060515593258 arthritis and atherosclerosis: imr.sagepub.com Focus on citrullination and carbamylation

Francesca Romana Spinelli, Arbi Pecani, Fabrizio Conti, Riccardo Mancini, Cristiano Alessandri and Guido Valesini

Abstract Coronary heart disease is the main cause of mortality in patients with (RA), a disease known to be associated with accelerated atherosclerosis. The role of inflammation and immunity in atherosclerotic process offers possible explanations for the increased cardiovascular risk in patients with RA. The immune response to citrullinated peptides has been extensively studied in RA; antibodies directed to citrullinated peptides are now a cornerstone for RA diagnosis. However, few studies have investigated the response to citrullinated peptides and the development of atherosclerotic plaque. Antibodies to carbamylated proteins can be detected before the clinical onset of RA, suggesting a potential predictive role for these antibodies; on the other hand, carbamylation of lipoproteins has been described in patients with cardiovascular disease. This review examines the role of citrullination and carbamylation, two post-translational protein modifications that appear to be involved in the pathogenesis of both RA and atherosclerosis, expanding the similarities between these two diseases. Further investigation on the role of the immune response to modified proteins may contribute to a better comprehension of cardiovascular disease in patients with RA.

Keywords Atherosclerosis, carbamylation, citrullination, post-translational modifications, rheumatoid arthritis Rheumatology Unit, Department of Internal Medicine and Medical Specialities, Sapienza University of Rome, Rome, Introduction Italy Rheumatoid arthritis (RA) is a systemic Corresponding author: inflammatory disease that has been shown Francesca Romana Spinelli, Rheumatology Unit, Department of Internal Medicine and Medical Specialties, to be associated with accelerated athero- 1 Sapienza University of Rome, Viale del Policlinico 155, sclerosis. Coronary heart disease (CHD) Rome 00161, Italy. represents a major cause of mortality in Email: [email protected]

Creative Commons CC-BY-NC:This article is distributed under the terms of the Creative Commons Attribution-NonCommercial 3.0 License (http://www.creativecommons.org/licenses/by-nc/3.0/) which permits non-commercial use, reproduction and distribution of the work without further permissionDownloaded provided from imr.sagepub.com the original work by guest is attributed on October as10,specified 2016 on the SAGE and Open Access page (https://us.sagepub.com/en-us/nam/open-access-at-sage). 82 Journal of International Medical Research 44(1S) patients with RA.1 The role of inflammation antibodies have a predictive role (as they can and immunity in the atherosclerotic process be detected before RA onset), and a prog- offers possible explanations for the increased nostic role, being associated with a particu- cardiovascular risk observed in RA patients. larly severe and erosive arthritis.3 Post-translational modifications encom- Anticitrullinated protein antibodies are pass a group of reactions that modify the implicated in the pathogenesis of RA. structure and extend the functions of pro- Citrullinated peptides bind human leuko- teins. Two of these modifications, citrullina- cyte antigen DRB1, the so-called shared tion and carbamylation, seem to be involved epitope, and a strong correlation between in the pathogenesis of both RA and athero- ACPA positivity and shared epitope expres- sclerosis, extending the links between the sion was demonstrated.4 Moreover, smok- two diseases. ing may induce an immune response to citrullinated peptides, with generation of ACPA and the onset of RA in shared- Citrullination and RA epitope carriers.5 Published data support Citrullination is an enzymatic post-transla- a link between RA and chronic periodon- tional modification that is mediated by titis; the oral pathogen Porphyromonas peptidylarginine deiminases (PAD), which gingivalis has the unique ability to produce transform peptide-bound residues a PAD enzyme that citrullinates proteins into , a non-natural .2 and may induce the development of RA in Over the past decade, the immune response genetically predisposed individuals.6 to citrullinated peptides has been extensively Interestingly, both cigarette smoking and studied in RA, and anticitrullinated protein P. gingivalis are also risk factors for cardio- antibodies (ACPA) are now a cornerstone vascular disease (Figure 1). The effect of for the diagnosis of RA, with a specificity of therapy on ACPA status remains 85–95% and a sensitivity of 68–79%.3 These controversial.4

Figure 1. Schematic representation of the shared pathogenic pathway linking rheumatoid arthritis and atherosclerosis.

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can be detected before the clinical onset of Citrullination and atherosclerosis RA, suggesting a potential predictive role Few studies have investigated the response to for these antibodies.12 The exact pathogenic citrullinated peptides and the development role of carbamylated proteins and the effect of atherosclerotic plaque. Sokolove et al.7 of RA treatment on antibodies to these demonstrated that both citrullinated fibrino- proteins remain unaddressed. gen and vimentin were correlated with the coronary artery calcium score in 134 female Carbamylation and patients with RA. Moreover, citrullinated proteins and PAD-4 enzyme were detected atherosclerosis within atherosclerotic plaques obtained Carbamylation of various lipoproteins has from non-RA patients, and ACPA isolated been described in patients with cardiovascu- from patients with RA were able to target lar disease. Carbamylated high-density lipo- these proteins.7 Citrullinated proteins and protein may promote atherogenesis by PAD enzymes have also been detected in the impairing the balance between macro- perivascular myocardial interstitium, espe- phage-mediated cholesterol uptake and cially in RA patients.8 Cambridge et al.9 efflux.13 Carbamylation of low-density lipo- investigated the possible association between protein (LDL) might induce endothelial ACPA and CHD in 432 healthy subjects who dysfunction, acting via the lectin-type oxi- were followed up for 5 years. In this study,9 a dized LDL receptor 1,14 a scavenger recep- significantly higher percentage of partici- tor for oxidized LDL that has been pants who developed CHD were ACPA- proposed as a of RA.15 positive compared with those who did not Carbamylated LDL may uncouple endothe- develop CHD; the association remained lial , reducing nitric significant even after adjustment for trad- oxide bioavailability and impairing endo- itional atherosclerotic risk factors.9 thelium vasodilatation.14 Moreover, carba- mylated LDL seems to promote monocyte adhesion to endothelial cells, damage endo- Carbamylation and RA thelial cells and progenitor endothelial cells, Carbamylation is a chemical post- and induce vascular smooth muscle-cell translational modification consisting of the proliferation.16 Carbamylation of other pro- addition of a cyanate group on self peptides, teins that are not yet clearly elucidated, may leading to the production of . also contribute to the pathogenesis of Among other factors, tobacco smoke seems atherosclerosis. to induce protein carbamylation.10 The immunogenicity of homocitrulline has been studied in RA patients. Shi et al.11 detected Conclusions antibodies to carbamylated proteins in both Citrullination and carbamylation are two ACPA-positive and -negative patients; in post-translational modifications that seem the latter group, carbamylated protein anti- to link RA and atherosclerosis, expanding body positivity was strongly associated with the similarities between these two inflamma- more erosive forms of RA compared with tory, immune-mediated chronic diseases. antibody negativity.11 Moreover, cross-reac- Further investigation into the role of tivity between antibodies to citrullinated the immune response against citrulline and homocitrullinated proteins seems to be and homocitrulline may contribute to a low.11 Similar to ACPA and rheumatoid better cardiovascular outcome in patients factor, antibodies to carbamylated proteins with RA.

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8. Giles JT, Fert-Bober J, Park JK, et al. Declaration of conflicting interest Myocardial citrullination in rheumatoid The authors declare that there are no conflicts of arthritis: a correlative histopathologic study. interest. Arthritis Res Ther 2012; 14: R39. 9. Cambridge G, Acharya J, Cooper JA, et al. Antibodies to citrullinated peptides and risk Funding of coronary heart disease. Atherosclerosis 2013; 228: 243–246. Editorial assistance was provided by Gayle 10. Roberts JM, Veres PR, Cochran AK, et al. Robins on behalf of HPS–Health Publishing in the atmosphere and its and Services Srl and funded by Pfizer Italia. possible link to smoke-related health effects. Proc Natl Acad Sci USA 2011; 108: References 8966–8971. 11. Shi J, Knevel R, Suwannalai P, et al. 1. Nurmohamed MT, Heslinga M and Kitas Autoantibodies recognizing carbamylated GD. Cardiovascular comorbidity in rheum- proteins are present in sera of patients with atic diseases. Nat Rev Rheumatol 2015; doi: rheumatoid arthritis and predict joint 10.1038/nrrheum.2015.112. damage. Proc Natl Acad Sci USA 2011; 108: 2. Gyo¨rgy B, To´th E, Tarcsa E, et al. 17372–17377. Citrullination: a posttranslational modifica- 12. Shi J, van de Stadt LA, Levarht EW, et al. tion in health and disease. Int J Biochem Cell Anti-carbamylated protein antibodies are Biol 2006; 38: 1662–1677. present in arthralgia patients and predict the 3. Aggarwal R, Liao K, Nair R, et al. Anti- development of rheumatoid arthritis. citrullinated peptide antibody assays and their Arthritis Rheum 2013; 65: 911–915. role in the diagnosis of rheumatoid arthritis. 13. Holzer M, Gauster M, Pfeifer T, et al. Arthritis Rheum 2009; 61: 1472–1483. Protein carbamylation renders high-density 4. Modi S, Soejima M and Levesque MC. The lipoprotein dysfunctional. Antioxid Redox effect of targeted rheumatoid arthritis thera- Signal 2011; 14: 2337–2346. pies on anti-citrullinated protein autoanti- 14. Speer T, Owala FO, Holy EW, et al. body levels and B cell responses. Clin Exp Carbamylated low-density lipoprotein Immunol 2013; 173: 8–17. induces endothelial dysfunction. Eur Heart J 5. Klareskog L, Stolt P, Lundberg K, et al. A 2014; 35: 3021–3032. new model for an etiology of rheumatoid 15. Ishikawa M, Ito H, Akiyoshi M, et al. arthritis: smoking may trigger HLA-DR Lectin-like oxidized low-density lipoprotein (shared epitope)-restricted immune reactions receptor 1 signal is a potent biomarker and to autoantigens modified by citrullination. therapeutic target for human rheumatoid Arthritis Rheum 2006; 54: 38–46. arthritis. Arthritis Rheum 2012; 64: 6. Koziel J, Mydel P and Potempa J. The link 1024–1034. between periodontal disease and rheumatoid 16. Jaisson S, Pietrement C and Gillery P. arthritis: an updated review. Curr Rheumatol Carbamylation-derived products: bioactive Rep 2014; 16: 408. compounds and potential biomarkers in 7. Sokolove J, Brennan MJ, Sharpe O, et al. chronic renal failure and atherosclerosis. Brief report: citrullination within the athero- Clin Chem 2011; 57: 1499–1505. sclerotic plaque: a potential target for the anti- citrullinated protein antibody response in rheumatoid arthritis. Arthritis Rheum 2013; 65: 1719–1724.

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