Uncoupling of the eNOS reaction. It is important to understand the role of endothelial dysfunction in accelerated atherosclerosis and even more important to understand the role of eNOS enzyme uncoupling and how it relates to MS, PD, T2DM, and non-diabetic atherosclerosis. Oxygen reacts with the eNOS enzyme in which the tetrahydrobiopertin (BH4) cofactor has coupled nicotinamide dinucleotide phosphate reduced (NAD(P)H) emzyme with L-arginine to be converted to nitric oxide (NO) and L-citrulline. When uncoupling occurs the NAD(P)H enzyme reacts with O2 and the endothelial cell becomes a net producer of superoxide (O2•) instead of the protective endothelial NO. This figure demonstrates the additional redox stress placed upon the arterial vessel wall and capillaries in patients with MS, PD, and overt T2DM.