Hydrogen sulphide pathway contributes to the enhanced human platelet aggregation in hyperhomocysteinemia Roberta d'Emmanuele di Villa Bianca1

Emma Mitidieri, Matteo N D Di Minno, Nicholas S. Kirkby, Timothy D. Warner, Giovanni Di Minno, Giuseppe Cirino, Raffaella Sorrentino

Research output: Contribution to journalArticlepeer-review

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 (H2S), through multiple steps involving cystathionine β-synthase and cystathionine γ-lyase. Here we have evaluated the involvement of H2S 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 H2S was significantly higher in either platelets or plasma compared with healthy volunteers. Interestingly, thromboxane A2 production was markedly increased in response to both NaHS or L-cysteine in platelets of healthy volunteers. The inhibition of phospholipase A2, cyclooxygenase, or blockade of the thromboxane receptor markedly reduced the effects of H2S. Finally, phosphorylated- phospholipase A2 expression was significantly higher in MTHFR++ carriers compared with healthy volunteers. In conclusion, the H2S pathway is involved in the prothrombotic events occurring in hyperhomocysteinemic patients.

Original languageEnglish
Pages (from-to)15812-15817
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume110
Issue number39
DOIs
Publication statusPublished - Sep 24 2013

Keywords

  • Aminooxyacetic acid
  • Cardiovascular events
  • DL-propargylglycine
  • H2S gaseous transmitter
  • Urinary 11-dehydro-TXB2

ASJC Scopus subject areas

  • General

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