However, under the chronic condition of the metabolic syndrome milieu described above, with its incident overexpression of vascular tissue iNOS and NADPH oxidase 4 that act to sustain increases in local ROS and RNS, the eNOS dimer also becomes uncoupled in part due to the ROS/RNS oxidation of BH4 (to BH2), changing eNOS enzymatic activity to attenuate NO and amplify O2− production. This evidence concerns the gene NOS2 and metabolic syndrome.