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

Proc Natl Acad Sci U S A. 2013 Sep 24;110(39):15812-7. doi: 10.1073/pnas.1309049110. Epub 2013 Sep 9.


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.

Keywords: DL-propargylglycine; H2S gaseous transmitter; aminooxyacetic acid; cardiovascular events; urinary 11-dehydro-TXB2.

MeSH terms

  • Adenosine Triphosphate / metabolism
  • Arachidonic Acid / metabolism
  • Blood Platelets / metabolism
  • Cyclic AMP / metabolism
  • Cystathionine beta-Synthase / metabolism
  • Cystathionine gamma-Lyase / metabolism
  • Group IV Phospholipases A2 / metabolism
  • Heterozygote
  • Humans
  • Hydrogen Sulfide / pharmacology*
  • Hyperhomocysteinemia / blood*
  • Hyperhomocysteinemia / urine
  • Methylenetetrahydrofolate Reductase (NADPH2) / genetics
  • Platelet Aggregation / drug effects*
  • Receptors, Thrombin / metabolism
  • Signal Transduction / drug effects*
  • Thromboxane B2 / analogs & derivatives
  • Thromboxane B2 / urine


  • Receptors, Thrombin
  • Arachidonic Acid
  • Thromboxane B2
  • 11-dehydro-thromboxane B2
  • Adenosine Triphosphate
  • Cyclic AMP
  • Methylenetetrahydrofolate Reductase (NADPH2)
  • Group IV Phospholipases A2
  • Cystathionine beta-Synthase
  • Cystathionine gamma-Lyase
  • Hydrogen Sulfide