Faculty, Staff and Student Publications

Language

English

Publication Date

12-1-2025

Journal

Biomedicine & Pharmacotherapy

DOI

10.1016/j.biopha.2025.118762

PMID

41252787

Abstract

Nitric oxide (NO) is a key gasotransmitter that binds to soluble guanylate cyclase (sGC), thereby stimulating cGMP production. Under disease conditions, reactive oxygen species disrupt this signaling by either: (1) scavenging NO, or (2) promoting heme-free, NO-insensitive apo-sGC due to impaired heme incorporation or oxidative damage. To counteract these conditions, two pharmacological approaches have emerged: sGC stimulators, which allosterically enhance sGC sensitivity to low NO levels; and sGC activators, which directly activate apo-sGC (heme-free sGC) by binding to its empty heme pocket, inducing a conformation that mimics NO-bound sGC. Thus, sGC stimulators are thought to target only sGC. Instead, we here show both in vitro and in vivo that sGC stimulators also modulate apo-sGC and - together with sGC activators - exert additive effects on apo-sGC. This newly identified activity of sGC stimulators on apo-sGC appears to be redox-sensitive. Indeed, when inactive sGC (ferric heme sGC) is generated by the commonly used oxidant 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ), the stimulatory effect of sGC stimulators is abolished. The potential in vivo relevance of this mechanism was further demonstrated in a mouse model of ischemic stroke, wherein sGC is known to be predominantly NO-insensitive, yet sGC stimulators remain protective. Altogether, these findings challenge the current pharmacological paradigm of sGC modulation, revealing that both sGC and apo-sGC can be stimulated by sGC stimulators, whereas sGC activators remain specific to apo-sGC. This expanded understanding highlights the therapeutic potential of sGC stimulators, both as standalone treatments and in combination with sGC activators.

Keywords

Soluble Guanylyl Cyclase, Animals, Enzyme Activators, Mice, Nitric Oxide, Humans, Male, Mice, Inbred C57BL, Cyclic GMP, Oxadiazoles, Oxidation-Reduction, Enzyme Activation, CGMP, Guanylate cyclase, SGC activator, SGC stimulator, Stroke

Published Open-Access

yes

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