Fig. 2.

Model showing how modulation of peroxide metabolism and cytosolic NADPH redox systems are hypothesized to regulate the balance between sGC-cGMP stimulation of PKG and thiol oxidation-dimerization activation of PKG in the context of their potential participation in the bovine pulmonary artery contractile response to hypoxia. Hypoxia appears to remove a H₂O₂-mediated relaxation, where H₂O₂ originates from SOD metabolizing Nox4 oxidase-derived superoxide (O₂^.−). This H₂O₂–elicited relaxation may originate from stimulation of PKG activity and/or by hypoxia reversing relaxing mechanisms controlled by cytosolic NADPH oxidation. In this model, the relaxing mechanisms removed by hypoxia potentially involve decreasing intracellular calcium [Ca²⁺]_I (e.g. through increased uptake by the SERCA pump and decreased Ca²⁺ influx) and suppressing the action of Ca²⁺ on the contractile apparatus through inhibiting Rho kinase activity. The model also includes potential mechanisms through which PKG dimerization could also participate in the cytosolic NADPH oxidation-associated relaxation of bovine coronary arteries to hypoxia. Other sources of superoxide generation may influence hypoxic responses through their conversion to peroxide, including superoxide which is secreted into the extracellular environment and metabolized by the extracellular form of SOD (ecSOD). GSH Px = glutathione peroxidase.