New insights into the role of soluble guanylate cyclase in blood pressure regulation

Abstract

Purpose of review: Nitric oxide (NO)-soluble guanylate cyclase (sGC)-dependent signaling mechanisms have a profound effect on the regulation of blood pressure (BP). In this review, we will discuss recent findings in the field that support the importance of sGC in the development of hypertension.

Recent findings: The importance of sGC in BP regulation was highlighted by studies using genetically modified animal models, chemical stimulators/activators and inhibitors of the NO/sGC signaling pathway, and genetic association studies in humans. Many studies further support the role of NO/sGC in vasodilation and vascular dysfunction, which is underscored by the early clinical success of synthetic sGC stimulators for the treatment of pulmonary hypertension. Recent work has uncovered more details about the structural basis of sGC activation, enabling the development of more potent and efficient modulators of sGC activity. Finally, the mechanisms involved in the modulation of sGC by signaling gases other than NO, as well as the influence of redox signaling on sGC, have been the subject of several interesting studies.

Summary: sGC is fast becoming an interesting therapeutic target for the treatment of vascular dysfunction and hypertension, with novel sGC stimulating/activating compounds as promising clinical treatment options.

Figure 1

Regulation of sGC activity. In the absence of any stimulating or activating factors, sGC converts guanosine triphosphate (GTP) to cGMP at a low basal catalytic rate (center, top line). sGC containing a prosthetic heme group with reduced iron (Fe²⁺) can be stimulated by NO and by heme-dependent sGC stimulators such as riociguat. NO and riociguat act synergistically to increase sGC activity several hundred-fold. Sustained NO stimulation and/or the presence of oxidative stress can lead to S-nitrosylation of sGC, which makes the enzyme insensitive to NO stimulation. Direct oxidation of the heme iron to the Fe³⁺ state also prohibits stimulation by NO as well as by the heme-dependent sGC stimulators. Heme oxidation can lead to loss of the heme cofactor from sGC, which renders the enzyme prone to ubiquitination and proteasomal degradation. A new class of sGC modulators known as the sGC activators (e.g. cinaciguat) selectively activates heme-oxidized and heme-free sGC, protecting it from degradation and increasing sGC activity by mimicking the NO-heme complex in the heme-binding pocket of sGC.