Details

Autor(en) / Beteiligte

• di Villa Bianca, Roberta d'Emmanuele
• Mitidieri, Emma
• Di Minno, Matteo N. D.
• Kirkby, Nicholas S.
• Warner, Timothy D.
• Di Minno, Giovanni
• Cirino, Giuseppe
• Sorrentino, Raffaella

Titel

Hydrogen sulphide pathway contributes to the enhanced human platelet aggregation in hyperhomocysteinemia

Ist Teil von

• Proceedings of the National Academy of Sciences - PNAS, 2013-09, Vol.110 (39), p.15812-15817

Ort / Verlag

United States: National Academy of Sciences

Erscheinungsjahr

2013

Quelle

Free E-Journal (出版社公開部分のみ）

Beschreibungen/Notizen

• 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 ₂S), through multiple steps involving cystathionine β-synthase and cystathionine γ-lyase. Here we have evaluated the involvement of H ₂S 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 ₂S 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 ₂S. Finally, phosphorylated–phospholipase A ₂ expression was significantly higher in MTHFR++ carriers compared with healthy volunteers. In conclusion, the H ₂S pathway is involved in the prothrombotic events occurring in hyperhomocysteinemic patients.