Release of active peptidylarginine deiminase into the circulation during acute inflammation induced by coronary artery bypass surgery
Received 18 December 2018
Accepted for publication 14 March 2019
Published 29 May 2019 Volume 2019:12 Pages 137—144
Checked for plagiarism Yes
Review by Single-blind
Peer reviewers approved by Dr Colin Mak
Peer reviewer comments 2
Editor who approved publication: Dr Ning Quan
Anne Vejlstrup,1 Ann Merete Møller,2 Claus Henrik Nielsen,1,3,* Dres Damgaard1,3,*
1Institute for Inflammation Research, Center for Rheumatology and Spine Diseases, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark; 2Department of Anaesthesiology, Herlev Hospital, Herlev, Denmark; 3Section for Periodontology, Microbiology and Community Dentistry, Department of Odontology, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
*These authors contributed equally to this work
Purpose: Peptidylarginine deiminase (PAD) catalyzes citrullination, a post-translational modification that can alter structure, function and antigenicity of proteins. Citrullination in the lungs due to smoking is believed to initiate an anti-citrulline immune response in rheumatoid arthritis. Citrullination in other inflamed organs has also been demonstrated, but it is not known whether smoking or inflammatory processes in general result in release of relevant amounts of PAD into the circulation with potential to cause citrullination of proteins at various anatomical sites. Coronary artery bypass grafting (CABG) using cardiopulmonary bypass (CPB) induces an acute systemic inflammation response. In the present study, we investigate whether smoking or acute systemic inflammation causes release of PAD into the circulation.
Patients and methods: This study included 36 patients with coronary heart disease (16 smokers and 20 non-smokers) undergoing CABG surgery with CPB. Circulating levels of PAD2 and PAD4, PAD activity, the neutrophil activation markers MPO, MMP-9 and lipocalin-2, the cytokines IL-6 and IL-10, and the chemokine CXCL8 were measured 2 hrs preoperatively and 2 hrs postoperatively.
Results: At baseline, serum PAD2 and PAD4 concentration did not differ between smokers and non-smokers. However, serum from non-smokers contained higher PAD activity than serum from smokers. Circulating PAD2 levels and PAD activity increased markedly in both groups after surgery, as did all neutrophil activation markers, cytokines and chemokine. PAD2 levels correlated with neutrophil activation markers, but not with cytokine and chemokine levels.
Conclusion: Blood levels of PAD2 did not differ significantly between smokers and non-smokers, but smokers had decreased PAD activity in the circulation. PAD2 levels and PAD activity increased in blood during inflammation induced by CABG with CPB. This suggests that acute inflammation, ischemia or reperfusion, or a combination of these, leads to systemic spreading of enzymatically active PAD, which may affect protein function and induce generation of citrullinated self-antigens.
Keywords: citrullination, peptidylarginine deiminase, PAD, inflammation, coronary artery bypass grafting, CABG, cardiopulmonary bypass, CPB
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