Fig. 5.
Reactive oxygen species-dependent mechanisms regulating NO bioavailability. A) H2O2 (potentially generated by Nox4) can increase eNOS expression via an unknown mechanism leading to increased NO production. B) & C) Oxidant-dependent activation of Nrf2 leads to increased transcription of eNOS (and therefore NO production) and DDAH. Increased DDAH expression in turn acts to reduce ADMA (a competitive inhibitor of NOS) levels resulting in increased NO production. D) H2O2 (potentially generated by Nox4) potentiates the activation of the PI3K/Akt signalling pathway which results in phosphorylation and activation of eNOS and increased NO production. E) O2- is capable of reacting with NO to form peroxynitrite which reduces the bioavailability of NO. F) Glutathionylation of eNOS under oxidative conditions and G) Oxidation of the eNOS co-factor, BH4, leads to eNOS uncoupling, reduced NO production and O2- production. The likely oxidant is O2- generated by Nox2. GSH: glutathione, GS: glutathionylation, Pi: phosphorylation, BH4: tetrahydrobiopterin, DDAH: dimethylarginine dimethylaminohydrolase, U.O: unidentified oxidant.