One possible mediator is H2O2, given that: 1) expression of the NADPH oxidase catalytic subunit Nox4, which can generate H2O2 even in the absence of SOD [33], is elevated in the aorta of mice with hyperhomocysteinemia [30]; 2) diet-induced hyperhomocysteineima is associated with increased H2O2 in cerebral arterioles [17]; and 3) it has been demonstrated that glutathione peroxidase-1, which catalytically eliminates H2O2, protects non-cerebral vessels from endothelial dysfunction in mice with diet-induced hyperhomocysteinemia [25,34]. The gene discussed is NOX4; the disease is hyperhomocysteinemia.