Factors influencing the soluble guanylate cyclase heme redox state in blood vessels

Soluble guanylate cyclase (sGC) plays an important role in maintaining vascular homeostasis, as an acceptor for the biological messenger nitric oxide (NO). However, only reduced sGC (with a ferrous heme) can be activated by NO; oxidized (ferric heme) and apo (absent heme) sGC cannot. In addition, the proportions of reduced, oxidized, and apo sGC change under pathological conditions. Although diseased blood vessels often show decreased NO bioavailability in the vascular wall, a shift of sGC heme redox balance in favor of the oxidized/apo forms can also occur. Therefore, sGC is of growing interest as a drug target for various cardiovascular diseases. Notably, the balance between NO-sensitive reduced sGC and NO-insensitive oxidized/apo sGC in the body is regulated in a reversible manner by various biological molecules and proteins. Many studies have attempted to identify endogenous factors and determinants that influence this redox state. For example, various reactive nitrogen and oxygen species are capable of inducing the oxidation of sGC heme. Conversely, a heme reductase and some antioxidants reduce the ferric heme in sGC to the ferrous state. This review summarizes the factors and mechanisms identified by these studies that operate to regulate the sGC heme redox state.