title: High homocysteine levels prevent via H2 S the CoCl2 -induced alteration of lymphocyte viability.
abstract: 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 (H2 S)-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 (A2 A R). We observed that: (i) hypoxic conditions lowered the intracellular concentration of HCy by increasing adenosine production, which resulted in high A2 A R 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 H2 S production; (iii) DL-propargylglycine that inhibits H2 S production abolished the HCy effect. Together, these data suggest that high HCy levels prevent, via H2 S production and the resulting down-regulation of A2 A R expression, the hypoxia-induced adenosinergic alteration of lymphocyte viability. We point out the relevance of these mechanisms in the pathophysiology of cardiovascular diseases.
authors.affiliation: UMR-MD2, Marseille Medical School, Aix-Marseille University and IRBA, Northern sector, Marseille, France.
authors.forename: Laurie
authors.initials: L
authors.lastname: Bruzzese
authors.affiliation: UMR-MD2, Marseille Medical School, Aix-Marseille University and IRBA, Northern sector, Marseille, France.|CNRS, Institut des Sciences Biologiques, France.
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Fenouillet
authors.affiliation: UMR-MD2, Marseille Medical School, Aix-Marseille University and IRBA, Northern sector, Marseille, France.|Laboratory of Biochemistry, Timone University Hospital, Marseille, France.
authors.forename: Julien
authors.initials: J
authors.lastname: Fromonot
authors.affiliation: UMR-MD2, Marseille Medical School, Aix-Marseille University and IRBA, Northern sector, Marseille, France.
authors.forename: Josée-Martine
authors.initials: JM
authors.lastname: Durand-Gorde
authors.affiliation: UMR-MD2, Marseille Medical School, Aix-Marseille University and IRBA, Northern sector, Marseille, France.
authors.forename: Jocelyne
authors.initials: J
authors.lastname: Condo
authors.affiliation: UMR-MD2, Marseille Medical School, Aix-Marseille University and IRBA, Northern sector, Marseille, France.
authors.forename: Nathalie
authors.initials: N
authors.lastname: Kipson
authors.affiliation: UMR-MD2, Marseille Medical School, Aix-Marseille University and IRBA, Northern sector, Marseille, France.|Laboratory of Biochemistry, Timone University Hospital, Marseille, France.
authors.forename: Giovanna
authors.initials: G
authors.lastname: Mottola
authors.affiliation: UMR-MD2, Marseille Medical School, Aix-Marseille University and IRBA, Northern sector, Marseille, France.|Cardiology Department, Timone University Hospital, Marseille, France.
authors.forename: Pierre
authors.initials: P
authors.lastname: Deharo
authors.affiliation: UMR-MD2, Marseille Medical School, Aix-Marseille University and IRBA, Northern sector, Marseille, France.|Laboratory of Biochemistry, Timone University Hospital, Marseille, France.
authors.forename: Régis
authors.initials: R
authors.lastname: Guieu
authors.affiliation: UMR-MD2, Marseille Medical School, Aix-Marseille University and IRBA, Northern sector, Marseille, France.|INSERM, France.
authors.forename: Jean
authors.initials: J
authors.lastname: Ruf
mesh_terms: D000241:Adenosine / Q000378:metabolism; D000328:Adult; D000480:Alkynes / Q000494:pharmacology; D015687:Cell Hypoxia / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D003035:Cobalt / Q000633:toxicity*; D005998:Glycine / Q000031:analogs & derivatives / Q000494:pharmacology; D006710:Homocysteine / Q000378:metabolism / Q000494:pharmacology*; D006801:Humans; D006862:Hydrogen Sulfide / Q000494:pharmacology*; D020138:Hyperhomocysteinemia / Q000378:metabolism; D008214:Lymphocytes / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism; D008875:Middle Aged; D008954:Models, Biological; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D000480:Alkynes; D006710:Homocysteine; D003035:Cobalt; C009055:propargylglycine; C018021:cobaltous chloride; D000241:Adenosine; D005998:Glycine; D006862:Hydrogen Sulfide
keywords: A2A receptor; CoCl2; H2S; adenosine; homocysteine; hypoxia; lymphocyte