Antioxidants, inflammation and cardiovascular disease

Figure 1 Regulatory circuits in inflammation and endothelial dysfunction. During inflammation, NADPH oxidase (NOX) produces high levels of reactive oxygen species (ROS). T cells and natural killer cells produce interferon-γ, which activates enzyme GTP-cyclohydrolase I (GTP-CH-I), indoleamine 2,3-dioxygenase (IDO) and inducible nitric oxide synthase (iNOS) in monocyte-derived macrophages (M) and dendritic cells (DC). In endothelial cells, endothelial NOS (eNOS) is constitutively expressed and GTP-CH-I produces tetrahydrobioterin (BH₄), which is a NOS cofactor. BH₄ deficiency leads to NOS uncoupling and superoxide anion (O₂^-) formation, which reacts with NO to form peroxynitrite (ONOO^-). In a vicious cycle, ONOO^- oxidizes BH₄. In M/DC, GTP-CH-I synthesizes neopterin at expense of BH₄, which contributes to the low activity of iNOS in human M/DC. Furthermore, NO is a reversible inhibitor of the immunoregulatory enzyme IDO. IDO degrades the essential amino acid tryptophan to kynurenine.