J Cell Mol Med. 2020;00:1–8. | 1 wileyonlinelibrary.com/journal/jcmm Received: 19 November 2019 | Accepted: 29 May 2020 DOI: 10.1111/jcmm.15527 ORIGINAL ARTICLE Homocysteine concentration and adenosine A 2A receptor production by peripheral blood mononuclear cells in coronary artery disease patients Pierre Deharo 1,2,3 | Marion Marlinge 1 | Clair Guiol 1 | Donato Vairo 1 | Julien Fromonot 1,2 | Patrick Mace 2 | Mohamed Chefrour 2 | Marguerite Gastaldi 1 | Laurie Bruzzese 1 | Melanie Gaubert 4 | Marine Gaudry 3 | Nathalie Kipson 1 | Christine Criado 1 | Thomas Cuisset 5 | Franck Paganelli 4 | Jean Ruf 1 | Regis Guieu 1,2 | Emmanuel Fenouillet 1,6 | Giovanna Mottola 1,2 This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited. © 2020 The Authors. Journal of Cellular and Molecular Medicine published by Foundation for Cellular and Molecular Medicine and John Wiley & Sons Ltd. Pierre Deharo, Marion Marlinge, Clair Guiol, Emmanuel Fenouillet, Giovanna Mottola: Participating equally to the work. 1 C2VN, INSERM, INRA, Aix Marseille University, Marseille, France 2 Laboratory of Biochemistry, Timone University Hospital, Marseille, France 3 Department of Vascular Surgery, Timone University Hospital, Marseille, France 4 Department of Cardiology, Hospital Nord, Marseille and C2VN, Marseille, France 5 Department of Cardiology, Timone University Hospital, Marseille, France 6 CNRS, Institut des Sciences Biologiques, Paris, France Correspondence Pierre Deharo, C2VN, INSERM, INRA, Aix Marseille University, Marseille, France. Email: pierre.deharo@ap-hm.fr Funding information Archantec Society, Aix Marseille University, AP-HM, and Bristol-Myers Squibb. Abstract Hyperhomocysteinemia is associated with coronary artery disease (CAD). The mech- anistic aspects of this relationship are unclear. In CAD patients, homocysteine (HCy) concentration correlates with plasma level of adenosine that controls the coronary circulation via the activation of adenosine A 2A receptors (A 2A R). We addressed in CAD patients the relationship between HCy and A 2A R production, and in cellulo the effect of HCy on A 2A R function. 46 patients with CAD and 20 control healthy sub- jects were included. We evaluated A 2A R production by peripheral blood mononu- clear cells using Western blotting. We studied in cellulo (CEM human T cells) the effect of HCy on A 2A R production as well as on basal and stimulated cAMP produc- tion following A 2A R activation by an agonist-like monoclonal antibody. HCy concen- tration was higher in CAD patients vs controls (median, range: 16.6 [7-45] vs 8 [5-12] µM, P < 0.001). A 2A R production was lower in patients vs controls (1.1[0.62-1.6] vs 1.53[0.7-1.9] arbitrary units, P < 0.001). We observed a negative correlation between HCy concentration and A 2A R production (r = −0.43; P < 0.0001), with decreased A 2A R production above 25 µM HCy. In cellulo, HCy inhibited A 2A R production, as well as basal and stimulated cAMP production. In conclusion, HCy is negatively associated with A 2A R production in CAD patients, as well as with A 2A R and cAMP production in cellulo. The decrease in A 2A R production and function, which is known to hamper coronary blood flow and promote inflammation, may support CAD pathogenesis. KEYWORDS A 2A receptor, adenosine, coronary artery disease, homocysteine