Figure 5.

Uncoupling of the eNOS enzyme results in the endothelium becoming a net producer of superoxide. This cartoon depicts many of the significant metabolic events leading to endothelial nitric oxide synthase (eNOS) enzyme uncoupling in the endothelium. Reactive oxygen species (ROS) and their oxidative effects of the requisite cofactor tetrahydrobiopterin (BH₄) result in eNOS uncoupling. Excessive oxidation of BH₄ resulting in the generation of BH₃ and BH₂ will not run the eNOS reaction to completion. Instead the reaction uncouples and shifts to the C terminal reductase domain and oxygen reacts with the nicotine adenine dinucleotide phosphorus reduced (NADPH) oxidase enzyme resulting in the generation of superoxide [O₂⁻]. These dynamic metabolic sequences, involving the uncoupling of the eNOS, reaction result in a proinflammatory, proconstrictive and prothrombotic endothelium, which contributes to endothelial dysfunction. Adapted and expanded with permission.17