HC metabolism and vascular dysfunction. HC is formed upon demethylation of methionine via S-adenosylmethionine (AdoMet) and S-adenosylhomocysteine (AdoHC). HC is eliminated in the methionine cycle by remethylation through the action of methionine synthase (MS), a vitamin B12–dependent enzyme. In this reaction, methyltetrahydrofolate (CH₃THF) serves as the methyl donor, and is formed from methylene tetrahydrofolate (CH₂THF) through the action of methyltetrahydrofolate reductase (MTHFR). CH₂THF is formed from tetrahydrofolate (THF), a folate derivative. Alternatively, HC can participate in transsulfuration in which it condenses with serine through the action of the vitamin B6-dependent enzyme, cystathionine-β-synthase (CBS). Cystathionine then splits into cysteine and α-ketobutyrate. HC can modify vascular cell function by forming a direct disulfide protein derivative, as in the case of the fibrinolytic receptor, annexin II; by inducing a prothrombotic phenotype through largely unknown mechanisms; or by undergoing auto-oxidation generating superoxide radicals (redox stress), leading to depletion of nitric oxide (NO^•) and expression of acute stress–related genes. Redox stress may also activate the proinflammatory transcription factor NF-κB, which may induce expression of TNF-α, RAGE/EN-RAGE, VCAM-1, tissue factor, and MMP-9. TNF-α may also induce activation and nuclear translocation of NF-κB.