Soluble Guanylate Cyclase

Abstract

HomeCirculationVol. 119, No. 21Soluble Guanylate Cyclase Free AccessEditorialPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessEditorialPDF/EPUBSoluble Guanylate CyclaseNot a Dull Enzyme Guido Boerrigter, MD and John C. BurnettJr, MD Guido BoerrigterGuido Boerrigter From the Cardiorenal Research Laboratory, Division of Cardiovascular Diseases, Departments of Medicine and Physiology, Mayo Clinic College of Medicine, Rochester, Minn. Search for more papers by this author and John C. BurnettJrJohn C. BurnettJr From the Cardiorenal Research Laboratory, Division of Cardiovascular Diseases, Departments of Medicine and Physiology, Mayo Clinic College of Medicine, Rochester, Minn. Search for more papers by this author Originally published18 May 2009https://doi.org/10.1161/CIRCULATIONAHA.109.860288Circulation. 2009;119:2752–2754Other version(s) of this articleYou are viewing the most recent version of this article. Previous versions: May 18, 2009: Previous Version 1 Arthur Kornberg, who shared with Severo Ochoa the 1959 Nobel Prize for Physiology or Medicine, stated in his autobiography that he had never met a dull enzyme.1 We strongly believe that soluble guanylate cyclase (sGC; E.C.4.6.1.2) is no exception to this.Article see p 2781Nitric oxide (NO) plays an important physiological role as a signaling molecule as well as a cytotoxic agent. It is produced by 3 distinct NO synthases, specifically endothelial, neuronal, and inducible NO synthase. In the vasculature, endothelial NO synthase plays an important role in vascular homeostasis because NO generated in endothelial cells promotes vascular smooth muscle cell relaxation and inhibits platelet aggregation. Importantly, bioavailability of NO can be reduced in cardiovascular diseases, a condition which has been termed “endothelial dysfunction.” This phenomenon provides a rationale for therapeutic intervention.The primary target of NO is sGC, which is a heterodimeric enzyme consisting of an α- and β-subunit and a prosthetic heme group, which is located in the β-subunit. The heme group contains a ferrous iron atom (Fe2+). Binding of NO to this iron changes the conformation of the enzyme and leads to a >100-fold increase in catalytic rate (ie, the conversion of guanosine triphosphate to the second messenger cyclic guanosine monophosphate [cGMP]). The NO-induced cGMP signal modulates intracellularly the activity of several effector molecules: cGMP-dependent protein kinases, cGMP-regulated phosphodiesterases, and cGMP-gated ion channels. Of note, both heme iron oxidation (Fe3+) and heme removal render sGC unresponsive to NO (Figure). These 2 conditions could therefore provide a mechanism for “vascular smooth muscle cell dysfunction” in cardiovascular disease states, which are often characterized by marked vasoconstriction either systemically or in specific organs. Download figureDownload PowerPointFigure. Schematic illustrating 3 different forms of soluble guanylate cyclase and their respective responsiveness to nitrovasodilators, sGC stimulators (eg, BAY 41–2272), and sGC activators (eg, cinaciguat [BAY 58–2667]). NO and nitrovasodilators only stimulate sGC, which contains the heme moiety with a ferrous iron (Fe2+); furthermore, NO and nitrovasodilators have cGMP-independent actions. BAY 41–2272 also activates only the NO-sensitive sGC but without the cGMP-independent actions of NO and nitrovasodilators. Cinaciguat activates heme-free sGC, which is insensitive to NO. The question marks indicate that little is known about the transition between the different forms, their prevalence in health and disease, and their potential restoration to the reduced NO-sensitive form.Therapeutic administration of exogenous NO mimetics such as organic nitrates has been used for more than a century.2 However, nitrates have potential disadvantages including the development of tolerance, cGMP-independent actions, protein nitrosation, and oxidative stress.3 Given this background, great interest met the report by Ko et al in 1994 that the benzylindazole YC-1 was able to activate sGC directly (ie, in an NO-independent manner).4 Using a structure-driven approach with YC-1 as a lead compound and a high-throughput screening method, Stasch et al identified 2 different classes of NO-independent sGC stimulators, one of which was heme dependent whereas the other was heme independent.5,6 Importantly, neither class was associated with the development of tolerance after long-term administration, and both classes were effective in nitrate-tolerant vessels.The first orally available sGC stimulator to be introduced in 2001 was BAY 41–272, the photolabeling of which suggested that it binds to a regulatory site on the α subunit of sGC.5 BAY 41–2272 activation of sGC is synergistic with NO, and a related compound, BAY 41–8543, prolonged the half-life of the nitrosyl-heme complex.7 BAY 41–2272 decreased blood pressure in rats, and it reduced systemic and renal vascular resistance and increased cardiac output and renal blood flow in canine experimental heart failure (HF).5,8 However, BAY 41–2272 did not reduce right atrial pressure in experimental HF, which would likely be desirable for a HF drug.8 Further research led to the development of riociguat (BAY 63–2521), a compound with improved oral pharmacokinetics that is currently in clinical development for the treatment of pulmonary arterial hypertension.9 Importantly, these NO-independent but heme-dependent sGC stimulators, like NO, do not activate sGC if the heme iron is oxidized or if the heme is absent.Cinaciguat, also known as BAY 58–2667, is an NO-independent and heme-independent sGC activator first described in 2002.6 Activation of sGC by cinaciguat was not synergistic with NO but only additive, and cinaciguat did not affect the half-life of the nitrosyl-heme complex.7 It should be noted here that nonnitrosylated heme can be considered an inhibitor of sGC activity whereas nitrosylated heme strongly activates the enzyme.10 Oxidation of the heme iron not only makes sGC unresponsive to NO, but it also facilitates removal of the heme, which promotes degradation of the enzyme.11 Cinaciguat seems to exclusively activate the heme-free sGC by binding in the heme pocket and thus changing the enzyme conformation, which not only activates sGC but also inhibits its degradation.11–13 Given that cinaciguat has demonstrated biological actions in health and disease, we have evidence that a significant pool of heme-free sGC exists in both physiological and pathophysiological conditions.6,11,14–16Importantly, Stasch et al demonstrated that in isolated vessels from different vascular disease models, responsiveness to conventional NO donors decreased whereas sensitivity to cinaciguat increased, consistent with a reduction in NO-responsive nonoxidized sGC and an increase in heme-free sGC. These findings demonstrate that, in addition to being a potential new drug, cinaciguat is also an interesting pharmacological tool. In canine experimental HF, cinaciguat had hemodynamic actions that were qualitatively identical to those seen with nitroglycerin, which included systemic and renal vasodilation, increase in cardiac output and renal blood flow, maintenance of renal function, and reduction in right atrial pressure.8,14 The difference in the venous versus arterial dilation seen with cinaciguat and BAY 41–2272 may be due to local metabolism, a higher prevalence of heme-free sGC in the venous circulation, and a higher endogenous NO availability in the arterial circulation.In the current issue of Circulation, Lapp et al provide the first data on the use of cinaciguat in human HF.16 Cinaciguat infusion showed promising cardiac unloading actions, with reductions in cardiac filling pressures and systemic and pulmonary vascular resistance and an increase in cardiac output. As discussed by the authors, this was a proof-of-concept study without a control group and therefore interpretation of symptomatic improvement is difficult. From a drug development perspective, the study by Lapp et al is another encouraging step forward, and the logical next step, a placebo-controlled, randomized, double blind, Phase IIb study, has already been started (ClinicalTrials.gov Identifier: NCT00559650).It should be noted, however, that clinical trials in acute decompensated HF are not necessarily straightforward, which can be illustrated with some recent examples. In the Vasodilator in the Management of Acute CHF (VMAC) trial, B-type natriuretic peptide (ie, Nesiritide) led to a significantly larger reduction in pulmonary capillary wedge pressure at 3 hours than placebo and nitroglycerin.17 However, the dosing, which included an initial bolus, was associated with an increased incidence of hypotension, which likely contributed to a signal for worsened renal outcomes.18 Indeed, the optimal and most meaningful end points for clinical trials in acute decompensated HF are unclear, and it is increasingly acknowledged that a relatively short-term treatment during hospitalization may not be able to affect long-term outcomes. Also, HF is a very heterogenous syndrome and not every patient is likely to benefit from every intervention. Therefore, patient selection for a clinical trial may be crucial. Indeed, the recent Preliminary Study of Relaxin in Acute Heart Failure (pre-RELAX-AHF) that evaluated the vasodilator hormone relaxin specifically targeted patients with mild to moderate renal insufficiency and systolic blood pressure >125 mm Hg (for comparison: an exclusion criterion in the VMAC trial was a systolic blood pressure <90 mm Hg).17,19 The best clinical indication for cinaciguat remains to be established.In the study by Lapp et al, cinaciguat was given as an intravenous drug in the setting of acute decompensated HF. Of similar interest would be a heme-independent sGC activator with good oral pharmacokinetics for the long-term treatment of patients with HF. Clinical trials in HF with long-term administration of conventional sGC stimulators (ie, nitrates) have been associated with improved outcomes despite their above-mentioned potential shortcomings. For example, the African American Heart Failure Trial (A-HeFT) most recently showed improved survival with a combination of isosorbide dinitrate and hydralazine in self-identified African Americans.20 These findings should be incentive for the pharmaceutical industry to develop orally available heme-independent sGC activators, which would enable us to assess chronic sGC activation in HF or other cardiovascular disease states without cGMP-independent actions or tolerance development. The Table provides an overview of previously reported heme-dependent and heme-independent sGC stimulators. Table. NO-Independent Stimulators of Soluble Guanylate CyclaseNO-Independent but Heme-Dependent sGC StimulatorsNO- and Heme-Independent sGC ActivatorsYC-1BAY 58–2667 (cinaciguat)CFM-1571BAY 60–2770BAY 41–2272HMR1766 (ataciguat)BAY 41–8543S3448BAY 63–2521 (riociguat)A-350619A-344905A-778935In summary, there is a truly unmet need for novel, safe, and effective therapies for acute decompensated HF. Advances in molecular pharmacology in the broad field of cGMP activators and modulators have clearly resulted in innovative molecules that are able to bypass impaired NO/sGC/cGMP signaling in models of endothelial–vascular smooth muscle dysfunction. The translational work of Lapp and coworkers should be viewed as a seminal step forward in taking such advances to the bedside. Continuing human trials in HF and other cardiovascular disease syndromes will tell us if we are headed in the right direction.The opinions expressed in this article are not necessarily those of the editors or of the American Heart Association.Sources of FundingThe authors are supported by National Institutes of Health grants HL07111 (to Dr Boerrigter) and HL36634 (to Dr Burnett) and by the Mayo Foundation.DisclosuresDr Burnett has received research grants from Bayer and Scios. He is chair of the Scientific Advisory Board of Nile Therapeutics.FootnotesCorrespondence to John C. Burnett, Jr, Marriott Family Professor of Cardiovascular Research, Cardiorenal Research Laboratory, Mayo Clinic and Foundation, Guggenheim 9, 200 First St SW, Rochester, MN 55905. E-mail [email protected] References 1 Kornberg A. For the Love of Enzymes: The Odyssey of a Biochemist. Cambridge, Mass: Harvard University Press; 1989.Google Scholar2 Brunton T. Use of nitrite of amyl in angina pectoris. Lancet. 1867; 2: 97–98.CrossrefGoogle Scholar3 Warnholtz A, Mollnau H, Heitzer T, Kontush A, Moller-Bertram T, Lavall D, Giaid A, Beisiegel U, Marklund SL, Walter U, Meinertz T, Munzel T. Adverse effects of nitroglycerin treatment on endothelial function, vascular nitrotyrosine levels and cGMP-dependent protein kinase activity in hyperlipidemic Watanabe rabbits. J Am Coll Cardiol. 2002; 40: 1356–1363.CrossrefMedlineGoogle Scholar4 Ko FN, Wu CC, Kuo SC, Lee FY, Teng CM. YC-1, a novel activator of platelet guanylate cyclase. Blood. 1994; 84: 4226–4233.CrossrefMedlineGoogle Scholar5 Stasch JP, Becker EM, Alonso-Alija C, Apeler H, Dembowsky K, Feurer A, Gerzer R, Minuth T, Perzborn E, Pleiss U, Schroder H, Schroeder W, Stahl E, Steinke W, Straub A, Schramm M. NO-independent regulatory site on soluble guanylate cyclase. Nature. 2001; 410: 212–215.CrossrefMedlineGoogle Scholar6 Stasch JP, Schmidt P, Alonso-Alija C, Apeler H, Dembowsky K, Haerter M, Heil M, Minuth T, Perzborn E, Pleiss U, Schramm M, Schroeder W, Schröder H, Stahl E, Steinke W, Wunder F. NO- and haem-independent activation of soluble guanylyl cyclase: molecular basis and cardiovascular implications of a new pharmacological principle. Br J Pharmacol. 2002; 136: 773–783.CrossrefMedlineGoogle Scholar7 Schmidt P, Schramm M, Schroder H, Stasch JP. Mechanisms of nitric oxide independent activation of soluble guanylyl cyclase. Eur J Pharmacol. 2003; 468: 167–174.CrossrefMedlineGoogle Scholar8 Boerrigter G, Costello-Boerrigter LC, Cataliotti A, Tsuruda T, Harty GJ, Lapp H, Stasch JP, Burnett JC Jr. Cardiorenal and humoral properties of a novel direct soluble guanylate cyclase stimulator BAY 41–2272 in experimental congestive heart failure. Circulation. 2003; 107: 686–689.LinkGoogle Scholar9 Grimminger F, Weimann G, Frey R, Voswinckel R, Thamm M, Bolkow D, Weissmann N, Muck W, Unger S, Wensing G, Schermuly RT, Ghofrani HA. First acute haemodynamic study of soluble guanylate cyclase stimulator riociguat in pulmonary hypertension. Eur Respir J. 2009; 33: 785–792.CrossrefMedlineGoogle Scholar10 Ignarro L, Wood K, Wolin M. Activation of purified soluble guanylate cyclase by protoporphyrin IX. Proc Natl Acad Sci U S A. 1982; 79: 2870–2873.CrossrefMedlineGoogle Scholar11 Stasch JP, Schmidt PM, Nedvetsky PI, Nedvetskaya TY, H SA, Meurer S, Deile M, Taye A, Knorr A, Lapp H, Muller H, Turgay Y, Rothkegel C, Tersteegen A, Kemp-Harper B, Muller-Esterl W, Schmidt HH. Targeting the heme-oxidized nitric oxide receptor for selective vasodilatation of diseased blood vessels. J Clin Invest. 2006; 116: 2552–2561.CrossrefMedlineGoogle Scholar12 Schmidt PM, Schramm M, Schroder H, Wunder F, Stasch JP. Identification of residues crucially involved in the binding of the heme moiety of soluble guanylate cyclase. J Biol Chem. 2004; 279: 3025–3032.CrossrefMedlineGoogle Scholar13 Roy B, Mo E, Vernon J, Garthwaite J. Probing the presence of the ligand-binding haem in cellular nitric oxide receptors. Br J Pharmacol. 2008; 153: 1495–1504.CrossrefMedlineGoogle Scholar14 Boerrigter G, Costello-Boerrigter LC, Cataliotti A, Lapp H, Stasch JP, Burnett JC Jr. Targeting heme-oxidized soluble guanylate cyclase in experimental heart failure. Hypertension. 2007; 49: 1128–1133.LinkGoogle Scholar15 Frey R, Muck W, Unger S, Artmeier-Brandt U, Weimann G, Wensing G. Pharmacokinetics, pharmacodynamics, tolerability, and safety of the soluble guanylate cyclase activator cinaciguat (BAY 58–2667) in healthy male volunteers. J Clin Pharmacol. 2008; 48: 1400–1410.CrossrefMedlineGoogle Scholar16 Lapp H, Mitrovic V, Franz N, Heuer H, Buerke M, Wolfertz J, Mueck W, Unger S, Wensing G, Frey R. Cinaciguat (BAY 58–2667) improves cardiopulmonary hemodynamics in patients with acute decompensated heart failure. Circulation. 2009; 119: 21:2781–2788.MedlineGoogle Scholar17 VMAC-Investigators. Intravenous nesiritide vs nitroglycerin for treatment of decompensated congestive heart failure: a randomized controlled trial. JAMA. 2002; 287: 1531–1540.MedlineGoogle Scholar18 Sackner-Bernstein JD, Skopicki HA, Aaronson KD. Risk of worsening renal function with nesiritide in patients with acutely decompensated heart failure. Circulation. 2005; 111: 1487–1491.LinkGoogle Scholar19 Teerlink JR, Metra M, Felker GM, Ponikowski P, Voors AA, Weatherley BD, Marmor A, Katz A, Grzybowski J, Unemori E, Teichman SL, Cotter G. Relaxin for the treatment of patients with acute heart failure (Pre-RELAX-AHF): a multicentre, randomised, placebo-controlled, parallel-group, dose-finding phase IIb study. Lancet. 2009; 373: 1429–1439.CrossrefMedlineGoogle Scholar20 Taylor AL, Ziesche S, Yancy C, Carson P, D'Agostino R Jr, Ferdinand K, Taylor M, Adams K, Sabolinski M, Worcel M, Cohn JN. Combination of isosorbide dinitrate and hydralazine in blacks with heart failure. N Engl J Med. 2004; 351: 2049–2057.CrossrefMedlineGoogle Scholar Previous Back to top Next FiguresReferencesRelatedDetailsCited By Six I, Guillaume N, Jacob V, Mentaverri R, Kamel S, Boullier A and Slama M (2022) The Endothelium and COVID-19: An Increasingly Clear Link Brief Title: Endotheliopathy in COVID-19, International Journal of Molecular Sciences, 10.3390/ijms23116196, 23:11, (6196) Mann D and Felker G (2021) Mechanisms and Models in Heart Failure, Circulation Research, 128:10, (1435-1450), Online publication date: 14-May-2021. Six I, Flissi N, Lenglet G, Louvet L, Kamel S, Gallet M, Massy Z and Liabeuf S (2020) Uremic Toxins and Vascular Dysfunction, Toxins, 10.3390/toxins12060404, 12:6, (404) Buglioni A and Burnett J (2016) New Pharmacological Strategies to Increase cGMP, Annual Review of Medicine, 10.1146/annurev-med-052914-091923, 67:1, (229-243), Online publication date: 14-Jan-2016. Mónica F, Bian K and Murad F (2016) The Endothelium-Dependent Nitric Oxide–cGMP Pathway Endothelium, 10.1016/bs.apha.2016.05.001, (1-27), . Noiri E and Minami K (2014) Nitric Oxide and Endothelial Dysfunction Studies on Pediatric Disorders, 10.1007/978-1-4939-0679-6_4, (55-69), . Conole D and Scott L (2013) Riociguat: First Global Approval, Drugs, 10.1007/s40265-013-0149-5, 73:17, (1967-1975), Online publication date: 1-Nov-2013. Zamani P and Greenberg B (2013) Novel Vasodilators in Heart Failure, Current Heart Failure Reports, 10.1007/s11897-012-0126-4, 10:1, (1-11), Online publication date: 1-Mar-2013. Lundgren J, Kylhammar D, Hedelin P and Rådegran G (2012) sGC stimulation totally reverses hypoxia-induced pulmonary vasoconstriction alone and combined with dual endothelin-receptor blockade in a porcine model, Acta Physiologica, 10.1111/j.1748-1716.2012.02445.x, 206:3, (178-194), Online publication date: 1-Nov-2012. Aronson D and Krum H (2012) Novel therapies in acute and chronic heart failure, Pharmacology & Therapeutics, 10.1016/j.pharmthera.2012.03.002, 135:1, (1-17), Online publication date: 1-Jul-2012. Taylor A (2012) Nitric Oxide Modulation as a Therapeutic Strategy in Heart Failure, Heart Failure Clinics, 10.1016/j.hfc.2011.11.002, 8:2, (255-272), Online publication date: 1-Apr-2012. Vita J (2011) Endothelial Function, Circulation, 124:25, (e906-e912), Online publication date: 1-Dec-2011. de Mel A, Murad F and Seifalian A (2011) Nitric Oxide: A Guardian for Vascular Grafts?, Chemical Reviews, 10.1021/cr200008n, 111:9, (5742-5767), Online publication date: 14-Sep-2011. Hingorany S and Frishman W (2011) Soluble Guanylate Cyclase Activation With Cinaciguat, Cardiology in Review, 10.1097/CRD.0b013e3181fc1c10, 19:1, (23-29), Online publication date: 1-Jan-2011. Boerrigter G, Costello-Boerrigter L and Burnett J (2011) Alterations in Renal Function in Heart Failure Heart Failure: A Companion to Braunwald's Heart Disease, 10.1016/B978-1-4160-5895-3.10018-X, (291-299), . Huang N, Fleissner F, Sun J and Cooke J (2010) Role of Nitric Oxide Signaling in Endothelial Differentiation of Embryonic Stem Cells, Stem Cells and Development, 10.1089/scd.2009.0417, 19:10, (1617-1626), Online publication date: 1-Oct-2010. Mitrovic V, Hernandez A, Meyer M and Gheorghiade M (2009) Role of guanylate cyclase modulators in decompensated heart failure, Heart Failure Reviews, 10.1007/s10741-009-9149-7, 14:4, (309-319), Online publication date: 1-Dec-2009. June 2, 2009Vol 119, Issue 21 Advertisement Article InformationMetrics https://doi.org/10.1161/CIRCULATIONAHA.109.860288PMID: 19451346 Originally publishedMay 18, 2009 KeywordsvasculaturepharmacologyEditorialsvasodilationheart failurenitric oxidePDF download Advertisement SubjectsCongenital Heart DiseasePharmacology