期刊
JOURNAL OF CELLULAR AND MOLECULAR MEDICINE
卷 20, 期 8, 页码 1411-1419出版社
WILEY
DOI: 10.1111/jcmm.12829
关键词
adenosine; A(2A) receptor; CoCl2; H2S; homocysteine; hypoxia; lymphocyte
资金
- AMU
- APHM, France
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-gamma-lyase involved in HCy catabolism. We then addressed the intracellular metabolic pathway of adenosine and HCy, and the role of the adenosine A(2A) receptor (A2AR). We observed that: (i) hypoxic conditions lowered the intracellular concentration of HCy by increasing adenosine production, which resulted in high A(2A)R expression and 30, 50-cyclic adenosine monophosphate production; (ii) increasing intracellular HCy concentration reversed the hypoxiainduced 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 A(2A)R expression, the hypoxia-induced adenosinergic alteration of lymphocyte viability. We point out the relevance of these mechanisms in the pathophysiology of cardiovascular diseases.
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