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. In this review, we will discuss recent findings in the field which support the importance of sGC in the development of hypertension. Recent findings The importance of sGC in blood pressure 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 treatment options in the clinic.

Nitric oxide–sensitive guanylyl cyclase stimulation improves experimental heart failure with preserved ejection fraction

“…Reduction of cGMP synthesis as a consequence of diminished NO bioavailability is followed by deficient NO-sensitive or soluble guanylyl cyclase (NOsGC) stimulation. The NO/cGMP pathway is pivotal for cardiac and vascular function (20)(21)(22)(23). NOsGC stimulators, which are independent of NO production, offer a potentially novel approach to increase cGMP levels.…”

Genome-Wide microRNA Binding Site Variation between Extinct Wild Aurochs and Modern Cattle Identifies Candidate microRNA-Regulated Domestication Genes

“…GUCA2B is an activator of guanylate cyclase (encoded by GUCY2C ), a membrane protein that modulates cyclic guanosine monophosphate (cGMP) levels, thereby regulating water homeostasis in the intestine and kidneys ( Kita et al, 1994 ; Sindic and Schlatter, 2006 ). Guanylate cyclase also has a well-characterized role in vasodilatation and blood pressure regulation ( Buys and Sips, 2014 ). Furthermore, a microarray analysis identified variation of GUCA2B expression levels in mice and shows that this variation has an effect on pregnancy and fertility ( McConaha et al, 2011 ).…”

Carbon disulfide. Just toxic or also bioregulatory and/or therapeutic?

“…94,95 Owing partially to their high concentrations and CS 2 's electrophilicity, such thiols must be considered likely targets or biological sinks for CS 2 . This interaction will strongly depend on the pK a of the specific thiol and on the local pH.…”

“…A number of specific functions have been elucidated; for example, NO plays a key role in regulating blood pressure via the activation of soluble-guanylyl cyclase (sGC). 2 Other known physiological functions are not yet as well understood, and the biological roles of these SMBs and of respective derivatives such as nitroxyl (HNO), peroxynitrite (ONOO -) and persulfides (R-SS -) continue to be the subjects of extensive biomedical research efforts. [1][2][3][4][5][6][7][8][9][10][11] If one were to envision an unidentified (so far) SMB in mammalian chemical biology, it may be appropriate to consider the shared properties of NO, CO, and H 2 S. All are relatively nonpolar but are partially soluble in aqueous and lipid systems; thus, they readily diffuse in physiological media via spatial concentration gradients.…”