Deconstructing endothelial dysfunction: soluble guanylyl cyclase oxidation and the NO resistance syndrome
J. Clin. Invest. Mark T. Gladwin, et al. 116:2330 doi:10.1172/JCI29807 [Go to this article.]

Figure 1
Oxidized and heme-free sGC is unresponsive to NO but activated by BAY 58-2667. Upon activation by shear stress or acetylcholine (ACh), endothelial NO is produced by eNOS. NO then diffuses to smooth muscle and binds to the reduced hemes (Fe²⁺ ferrous heme) on the α/β heterodimer sGC, which in turn converts GTP to cGMP and leads to downstream smooth muscle relaxation and vasodilation. Clinical states of endothelial dysfunction can be associated with the accumulation of oxidized (Fe³⁺ ferric heme) and heme-free sGC that cannot be activated by NO. A study in this issue of the JCI demonstrates that the NO-and heme-independent activator of sGC, BAY 58-2667, can potently bind to and activate the oxidized and heme-free sGC, producing vasodilation of diseased blood vessels, while the porphyrin ligand protoporphyrin IX (PPIX) only binds to heme-free sGC (9). M, muscarinic receptor.