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Review
. 2011 May 24;123(20):2263-73.
doi: 10.1161/CIRCULATIONAHA.110.981738.

Soluble guanylate cyclase as an emerging therapeutic target in cardiopulmonary disease

Johannes-Peter Stasch  1 , Pál Pacher, Oleg V Evgenov
Affiliations
Review

Soluble guanylate cyclase as an emerging therapeutic target in cardiopulmonary disease

Johannes-Peter Stasch et al. Circulation. .
No abstract available

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Figures

Figure 1
Figure 1
Soluble guanylate cyclase (sGC) stimulators and activators target two different redox states of sGC, the nitric oxide (NO)-sensitive reduced (ferrous) sGC and NO-insensitive oxidized (ferric) sGC, respectively. Stimulators of sGC stabilize the nitrosyl-heme complex of the reduced sGC and exhibit a strong synergism with NO. In various pathophysiological conditions (such as heart failure, pulmonary and systemic hypertension, atherosclerosis, and ischemia-reperfusion injury), the sGC redox equilibrium can be shifted to the oxidized, ferric state by reactive oxygen species, and/or sGC can become heme-deficient. Activators of sGC bind to the unoccupied heme-binding complex or displace the prosthetic heme of sGC and produce only an additive effect with NO. In certain cases, sGC activators also protect sGC from proteasomal degradation. BH4, tetrahydrobiopterin; BH2, dihydrobiopterin; cGMP, cyclic guanosine monophosphate; eNOS, endothelial nitric oxide synthase; O2•−, superoxide; ONOO−, peroxynitrite; NADPH, nicotinamide adenine dinucleotide phosphate.
Figure 2
Figure 2
Pharmacological targets in the nitric oxide (NO)-soluble guanylate cyclase (sGC) signaling pathway in pulmonary hypertension. Pulmonary hypertension is associated with reduced levels of endogenous NO, as a result of decreased bioavailability of L-arginine due to increased activity of arginase, downregulation or uncoupling of the endothelial NO synthase (eNOS), inactivation of NO by superoxide anion, or increased plasma concentrations of the endogenous eNOS inhibitor asymmetric dimethylarginine (ADMA). Although the total sGC expression is increased (due to a marked increase in the expression of the heme-free form of sGC), alteration of the redox state of sGC through oxidative stress may lead to reduced levels of the NO-sensitive form of sGC. Phosphodiesterase (PDE) 5 inhibitors increase intracellular levels of cyclic guanosine monophosphate (cGMP) by reducing its hydrolysis, and therefore depend on sufficient upstream NO-cGMP signaling. By contrast, sGC stimulators increase cGMP production rather than preventing its degradation, and their downstream effects are not limited by low NO levels. PKG, protein kinase G.
Figure 3
Figure 3
Timeline of key events in the preclinical and clinical development of soluble guanylate cyclase stimulators. The discovery and first characterization of each compound is shown below the timeline. Key publications and trials are summarized above the timeline. Results are awaited from a phase II trial of riociguat in PH-COPD (ClinicalTrials.gov ID: NCT00640315), and phase III trials in CTEPH and PAH are ongoing (ClinicalTrials.gov ID: NCT00855465 and NCT00810693). Two phase II trials are also ongoing in PH-LHD, in patients with left ventricular diastolic and systolic dysfunction, respectively (ClinicalTrials.gov ID: NCT01172756 and NCT01065454). CTEPH, chronic thromboembolic pulmonary hypertension; NO, nitric oxide; PAH, pulmonary arterial hypertension; PH, pulmonary hypertension; PH-COPD, PH associated with chronic obstructive pulmonary disease; PH-ILD, PH associated with interstitial lung disease; PH-LHD, PH associated with left heart disease.
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