Table 1.

Redox processes modulating vascular cGMP signaling

Redox Species & Systems	Mechanisms Regulating cGMP Signaling
Nitric oxide (NO)	NO binds the Fe2+ heme of soluble guanylate cyclase (sGC) promoting cGMP generation and cGMP-mediated Protein Kinase G (PKG) activation
Superoxide	Superoxide reacts with NO forming peroxynitrite and RNS
Hydrogen Peroxide (H2O2)	Peroxide metabolism by Peroxiredoxin-1 promotes cGMP-independent PKG1α activation by disulfide formation between its subunits, a process inhibited by cGMP Peroxide metabolism by catalase promotes cGMP generation by sGC, a process inhibited by NO.
Reactive Nitrogen Species (RNS)	Peroxynitrite oxidizes the heme of Fe2+sGC, preventing its activation by NO Peroxynitrite and RNS formation may have additional effects oxidizing thiols and other functional groups in ways that may generate molecules that subsequently release NO in a delayed time-dependent manner.
Heme	Oxidation of the heme of Fe2+sGC prevents its activation by NO and promotes proteolytic depletion of sGC Physiological porphyrins such as protoporphyrin IX (PpIX) and Zn-PpIX potentially prevent the depletion of heme oxidized sGC
Thiols	Reduced thiols can be associated with enabling NO stimulation of sGC and minimizing cGMP-independent PKG1α activation by disulfide formation.
NADPH	Cytosolic NADPH may control the maintenance of the sGC heme in its Fe2+ form and reduced thiols needed for stimulation by NO. NADPH has a major role in influencing ROS regulation of sGC and PKG by its being a key source of electrons for superoxide and peroxide generation by Nox oxidases, and by its role in maintaining the reduced thiol status of key systems such as glutathione and thioredoxin which are used to consume peroxides. Cytosolic NADPH generated by glucose-6-phosphate dehydrogenase and the pentose phosphate pathway of glucose metabolism has a major role in maintained the reduced thiol status of PKG1α, and oxidation of NADPH promotes cGMP-independent PKG1α activation by disulfide formation