Targeting Soluble Guanylyl Cyclase during Ischemia and Reperfusion

Abstract

Ischemia and reperfusion (IR) damage organs and contribute to many disease states. Few effective treatments exist that attenuate IR injury. The augmentation of nitric oxide (NO) signaling remains a promising therapeutic target for IR injury. NO binds to soluble guanylyl cyclase (sGC) to regulate vasodilation, maintain endothelial barrier integrity, and modulate inflammation through the production of cyclic-GMP in vascular smooth muscle. Pharmacologic sGC stimulators and activators have recently been developed. In preclinical studies, sGC stimulators, which augment the reduced form of sGC, and activators, which activate the oxidized non-NO binding form of sGC, increase vasodilation and decrease cardiac, cerebral, renal, pulmonary, and hepatic injury following IR. These effects may be a result of the improved regulation of perfusion and decreased oxidative injury during IR. sGC stimulators are now used clinically to treat some chronic conditions such as heart failure and pulmonary hypertension. Clinical trials of sGC activators have been terminated secondary to adverse side effects including hypotension. Additional clinical studies to investigate the effects of sGC stimulation and activation during acute conditions, such as IR, are warranted.

Keywords: cardioprotection; ischemia reperfusion injury; neuroprotection; oxidative injury; sGC; sGC activator; sGC stimulator; soluble guanylyl cyclase; vasodilation.

Figure 1

Regulation of vasodilation by nitric oxide and soluble guanylyl cyclase. Nitric oxide (NO) is generated in the endothelium, diffuses into smooth muscle, binds to soluble guanylyl cyclase (sGC), where it induces a conformational change that catalyzes the generation cyclic guanosine monophosphate (cGMP). cGMP activates subsequent kinases resulting in vasodilation. Phosphodiesterase 5 (PDE–5) metabolizes cGMP. Hypoxia and shear stress stimulate endothelium-mediated vasodilation, whereas hyperoxia, oxidative damage, and trauma impair NO–mediated vasodilation.

Figure 2

Soluble guanylyl cyclase (sGC) stimulators and activators. sGC stimulators and nitric oxide (NO) bind to reduced heme (Fe²⁺) sGC, whereas sGC activators preferentially bind and activate oxidized (Fe³⁺) sGC. sGC activators can also activate the reduced heme enzyme but to a lesser extent. sGC catalyzes the production of cyclic guanosine monophosphate (cGMP) from guanosine triphosphate (GTP), resulting in vasodilation.