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    • Prolonged sGC oxidative inhibition occurs in many

    2022-05-20

    Prolonged sGC oxidative inhibition occurs in many diseases [46,[86], [87], [88]]. Keeping sGC membrane-bound and functional under conditions of high oxidative stress requires a mechanism for restoring oxidized sGC (Fe3+) heme iron to its reduced (Fe2+) state. Without this redox regulation, the sGC enzyme is NO-insensitive, irrespective of the proximal NO concentrations. How this redox regulation occurs was largely unknown until recently, when it was discovered that Cyb5R3 plays a central role in this process, as previously discussed [45]. Proximity ligation studies found oxidized sGC β associated with Cyb5R3 in rat aortic smooth muscle cell preps [45]. Using genetic and pharmacological interventions, purified Cyb5R3 and sGC were found to associate via the cyclase's ferric heme iron (Fe3+), forming a protein-protein complex that facilitates specific and coordinated ionophore transfer for reducing the sGC back to its ferrous (Fe2+) state [45]. The symbiotic interaction of these requisite activities necessitates the microdomain localization of sGC, not just for compartmentalized signaling, but also for optimal recycling of its heme iron by the reductase activity of Cyb5R3 (Fig. 3).
    Stimulators and activators of sGC Given that sGC has been shown to localize to the cell membrane and that dysregulation of the sGC signaling pathway has been associated with hypertension and cardiovascular disease, several stimulators and activators of sGC have been developed as therapeutics. The sGC stimulators and activators have distinct mechanisms of action. sGC stimulators increase sGC activity only when the heme iron is in the reduced state (Fe2+) while sGC activators increase enzymatic activity of the oxidized heme iron (Fe3+) or heme deficient apo-sGC. One of the earliest stimulators, YC-1, was responsible for sensitizing sGC to CO, allowing it to stimulate sGC in a manner similar to NO [89]. YC-1 potentiated CO- and NO-induced sGC activity, as well as protoporphyrin IX NO-independent activation of sGC, indicating that YC-1 may stabilize the enzyme's active configuration [89]. Another extensive study of YC-1 found that YC-1 synergistically activated sGC with sodium nitroprusside [90]. The greatly increased cGMP levels and subsequent vasorelaxation were inhibited by the exogenous sGC inhibitor NS 2028 [90]. While most of the previous literature had focused on the heme-dependent characteristics of YC-1, the compound's stimulatory activity on sGC was only partially attenuated by ODQ-mediated oxidation of sGC heme, indicating a heme-independent action for YC-1 [91]. Another partially NO-independent stimulator of sGC, BAY 41-2272, was originally found to increase sGC activity via a regulatory region on the α1 subunit between the Cys 238 and Cys 243 regions [92,93] while also further sensitizing the enzyme to NO [94]. However, more recent studies indicate that Bay 41-2272 may bind to the β1 H-NOX domain [95]. BAY 41-2272 was shown to have in vivo dose-dependent blood pressure lowering effects in anesthetized dogs and conscious hypertensive rats [96]. With similar potency to BAY 41-2272, BAY 63-2521 (Riociguat) also showed stimulatory activity on sGC and the absence of the unfavorable metabolic and pharmacokinetic side effects observed with other drugs in its class that have been used in the treatment of pulmonary hypertension [97]. Vasodilation by Riociguat also occurred synergistically with NO [97]. With a growing focus on developing drugs targeting sGC to treat cardiovascular conditions, Vericiguat (BAY 1021189) is a recently discovered sGC stimulator used to treat chronic heart failure [98]. It has a longer half-life than its predecessor Riociguat, requiring less frequent dosing throughout the day [98]. IWP-051 joins the list of therapeutics for cardiovascular disease, functioning via sGC stimulator activity that is potent, stable, and selective in avoiding off-target liabilities such as phosphodiesterase activities [99]. An analog of acrylamide, A-778935, in synergy with sodium nitroprusside, also strongly stimulated sGC [100]. ODQ competitively inhibited A-778935, which was unable to activate heme-deficient sGC, indicating that A-778935 activation of sGC was heme-dependent [100]. It is possible that ODQ oxidized heme can induce protein conformational changes [93] or cause steric hindrance at the A-778935 binding site on sGC, altering the response to A-778935 [100]. Several variants to sGC stimulators, such as BAY 41-2272 and Vericiguat, have been relatively successfully used to treat pulmonary hypertension and heart failure. However, a major limitation of these drugs is the reliance on a reduced heme state in sGC or the presence of an electron donor. Therefore, despite the popularity and potential efficacy of stimulators in treating cardiovascular diseases, alternative approaches to sGC targeting have been developed to combat such limitations.