High homocysteine levels prevent via H 2 S the CoCl 2 ‐induced alteration of lymphocyte viability

High homocysteine ( HC y) 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 HC y, we addressed the influence of high HC y 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 (CoCl 2 )to reproduce hypoxia. We found that CoCl 2 ‐altered cell viability was dose‐dependently reversed using HC y. In turn, the HC y effect was inhibited using DL ‐propargylglycine, a specific inhibitor of the hydrogen sulphide (H 2 S)‐synthesizing enzyme cystathionine‐γ‐lyase involved in HC y catabolism. We then addressed the intracellular metabolic pathway of adenosine and HC y, and the role of the adenosine A 2A receptor (A 2 A R ). We observed that: ( i ) hypoxic conditions lowered the intracellular concentration of HC y by increasing adenosine production, which resulted in high A 2 A R expression and 3′, 5′‐cyclic adenosine monophosphate production; ( ii ) increasing intracellular HC y concentration reversed the hypoxia‐induced adenosinergic signalling despite high adenosine concentration by promoting both S‐adenosylhomocysteine and H 2 S production; ( iii ) DL ‐propargylglycine that inhibits H 2 S production abolished the HC y effect. Together, these data suggest that high HC y levels prevent, via H 2 S production and the resulting down‐regulation of A 2 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.