Potential Roles of Endoplasmic Reticulum Stress and Cellular Proteins Implicated in Diabesity

Figure 2

eNOS, NADPH, and ER stress consequential generation of NO and superoxide anion from coupled and uncoupled NOS. eNOS requires substrates such as oxygen, BH₄ cofactors, L-arginine, NADPH, FMN, and heme. In the physiological circumstances, the availability of BH₄ is sustained by guanosine triphosphate (GTP), such that the rate-limiting step is catalyzed by GTP cyclohydrolase I (GTPCH). The enzyme dihydrofolate reductase (DHFR) mediates the reprocessing of BH₂ to produce BH₄ as the primary nonenzymatic oxidation. eNOS uncoupling leads to the generation of superoxide anion. The superoxide anion produced results in decreased bioavailability of BH₄. As such, superoxide anions generated owing to uncoupled eNOS reacts with NO to produce ONOO-, a highly reactive anion that quickly oxidizes BH₄. Furthermore, self-propagating oxidative stress can stabilize eNOS uncoupling. Other demonstrated mechanisms that enhance the uncoupling of eNOS include high concentrations of endogenous NO synthase inhibitors, increased levels of oxidized glutathione relative to decreased glutathione, and reduced availability of arginine. BH2: dihydrobiopterin; BH4: tetrahydrobiopterin; DHFR: dihydrofolate reductase; OS: oxidative stress; NO: nitric oxide; eNOS: endothelial nitric oxide synthase; NADPH: nicotinamide adenine dinucleotide phosphate; ONOO-: peroxynitrite; L-NMMA: NG-monomethyl-L-arginine; ADMA: asymmetric dimethylarginine; GSSG: oxidized glutathione; GSH: reduced glutathione.