In:
Proceedings of the National Academy of Sciences, Proceedings of the National Academy of Sciences, Vol. 110, No. 39 ( 2013-09-24), p. 15812-15817
Abstract:
Homocysteine is metabolized to methionine by the action of 5,10 methylenetetrahydrofolate reductase (MTHFR). Alternatively, by the transulfuration pathway, homocysteine is transformed to hydrogen sulphide (H 2 S), through multiple steps involving cystathionine β-synthase and cystathionine γ-lyase. Here we have evaluated the involvement of H 2 S in the thrombotic events associated with hyperhomocysteinemia. To this purpose we have used platelets harvested from healthy volunteers or patients newly diagnosed with hyperhomocysteinemia with a C677T polymorphism of the MTHFR gene (MTHFR++). NaHS (0.1–100 µM) or l -cysteine (0.1–100 µM) significantly increased platelet aggregation harvested from healthy volunteers induced by thrombin receptor activator peptide–6 amide (2 µM) in a concentration-dependent manner. This increase was significantly potentiated in platelets harvested from MTHFR++ carriers, and it was reversed by the inhibition of either cystathionine β-synthase or cystathionine γ-lyase. Similarly, in MTHFR++ carriers, the content of H 2 S was significantly higher in either platelets or plasma compared with healthy volunteers. Interestingly, thromboxane A 2 production was markedly increased in response to both NaHS or l -cysteine in platelets of healthy volunteers. The inhibition of phospholipase A 2 , cyclooxygenase, or blockade of the thromboxane receptor markedly reduced the effects of H 2 S. Finally, phosphorylated–phospholipase A 2 expression was significantly higher in MTHFR++ carriers compared with healthy volunteers. In conclusion, the H 2 S pathway is involved in the prothrombotic events occurring in hyperhomocysteinemic patients.
Type of Medium:
Online Resource
ISSN:
0027-8424
,
1091-6490
DOI:
10.1073/pnas.1309049110
Language:
English
Publisher:
Proceedings of the National Academy of Sciences
Publication Date:
2013
detail.hit.zdb_id:
209104-5
detail.hit.zdb_id:
1461794-8
SSG:
11
SSG:
12
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