High homocysteine levels prevent via H2S the CoCl2-induced alteration of lymphocyte viability

Laurie Bruzzese (1) , Emmanuel Fenouillet (2, 1) , Julien Fromonot (3, 1) , Jm Durand-Gorde (1) , Jocelyne Condo (1) , Nathalie Kipson (1) , Giovana Mottola (1, 3) , Pierre Deharo (1, 3) , Régis Guieu (1, 3) , Jean Ruf (4, 1)

1 DS-ACI / UMR MD2 - Dysoxie, suractivité : aspects cellulaires et intégratifs thérapeutiques
2 Institut des Sciences Biologiques du CNRS
3 TIMONE - Hôpital de la Timone [CHU - APHM]
4 INSERM - Institut National de la Santé et de la Recherche Médicale

High homocysteine (HCy) levels are associated with lymphocyte-mediated inflammatory responses that are sometimes in turn related to hypoxia. Because adenosine is a potent lymphocyte suppressor produced in hypoxic conditions and shares metabolic pathways with HCy, we addressed the influence of high HCy levels on the hypoxia-induced, adenosine-mediated, alteration of lymphocyte viability. We treated mitogen-stimulated human lymphocytes isolated from healthy individuals and the human lymphoma T-cell line CEM with cobalt chloride (CoCl2)to reproduce hypoxia. We found that CoCl2-altered cell viability was dose-dependently reversed using HCy. In turn, the HCy effect was inhibited using DL-propargylglycine, a specific inhibitor of the hydrogen sulphide (H2S)-synthesizing enzyme cystathionine-γ-lyase involved in HCy catabolism. We then addressed the intracellular metabolic pathway of adenosine and HCy, and the role of the adenosine A2A receptor (A2AR). We observed that: (i) hypoxic conditions lowered the intracellular concentration of HCy by increasing adenosine production, which resulted in high A2AR expression and 3′, 5′-cyclic adenosine monophosphate production; (ii) increasing intracellular HCy concentration reversed the hypoxia-induced adenosinergic signalling despite high adenosine concentration by promoting both S-adenosylhomocysteine and H2S production; (iii) DL-propargylglycine that inhibits H2S production abolished the HCy effect. Together, these data suggest that high HCy levels prevent, via H2S production and the resulting down-regulation of A2AR expression, the hypoxia-induced adenosinergic alteration of lymphocyte viability. We point out the relevance of these mechanisms in the pathophysiology of cardiovascular diseases.

Domaines: Sciences du Vivant [q-bio]

Laurie Bruzzese, Emmanuel Fenouillet, Julien Fromonot, Jm Durand-Gorde, Jocelyne Condo, et al.. High homocysteine levels prevent via H2S the CoCl2-induced alteration of lymphocyte viability. Journal of Cellular and Molecular Medicine, 2016, ⟨10.1111/jcmm.12829⟩. ⟨hal-01307326⟩