Skip to main content

Advertisement

SpringerLink
Log in

cGMP: transition from bench to bedside: a report of the 6th International Conference on cGMP Generators, Effectors and Therapeutic Implications

  • Review
  • Published:
Naunyn-Schmiedeberg's Archives of Pharmacology Aims and scope Submit manuscript

Abstract

Essential physiological homeostatic processes such as vascular tone, fluid balance, cardiorenal function, and sensory processes are regulated by the second messenger cyclic guanosine 3′, 5′-monophosphate (cGMP). Dysregulation of cGMP-dependent pathways plays an important role in cardiovascular diseases such as hypertension, pulmonary hypertension, heart failure, or erectile dysfunction. Thus, the cGMP pathway consisting of the cGMP-generating guanylyl cyclases, protein kinases, and phosphodiesterases (PDE) has evolved to an important drug target and is the focus of a wide variety of research fields ranging from unraveling mechanisms on the molecular level to understanding the regulation of physiological and pathophysiological processes by cGMP. Based on the results from basic and preclinical research, therapeutic drugs have been developed which modulate the cGMP pathway and are investigated in clinical trials. Riociguat, a nitric oxide (NO)-independent soluble guanylyl cyclase stimulator; recombinant B-type natriuretic peptide (BNP); or recombinant atrial natriuretic peptide (ANP) and PDE5 inhibitors are cGMP-modulating drugs that are already available for the treatment of pulmonary hypertension, acute heart failure, and erectile dysfunction, respectively. The latest results from basic to clinical research on cGMP were presented on the 6th International Conference on cGMP in Erfurt, Germany, and are summarized in this article.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1

Similar content being viewed by others

References

  • Allerston CK, von Delft F, Gileadi O (2013) Crystal structures of the catalytic domain of human soluble guanylate cyclase. PLoS One 8:e57644

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Andersen MJ et al (2013) Sildenafil and diastolic dysfunction after acute myocardial infarction in patients with preserved ejection fraction: the Sildenafil and Diastolic Dysfunction After Acute Myocardial Infarction (SIDAMI) trial. Circulation 127:1200–1208

    Article  CAS  PubMed  Google Scholar 

  • Arora P et al (2013) Atrial natriuretic peptide is negatively regulated by microRNA-425. J Clin Invest 123:3378–3382

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Bordicchia M et al (2012) Cardiac natriuretic peptides act via p38 MAPK to induce the brown fat thermogenic program in mouse and human adipocytes. J Clin Invest 2012

  • Cannone V et al (2011) A genetic variant of the atrial natriuretic peptide gene is associated with cardiometabolic protection in the general community. J Am Coll Cardiol 58:629–636

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Cannone V et al (2013) The atrial natriuretic peptide genetic variant rs5068 is associated with a favorable cardiometabolic phenotype in a Mediterranean population. Diabetes 36:2850–2856

    CAS  Google Scholar 

  • Chen HH, Grantham JA, Schirger JA, Jougasaki M, Redfield MM, Burnett JC Jr (2000) Subcutaneous administration of brain natriuretic peptide in experimental heart failure. J Am Coll Cardiol 36:1706–1712

    Article  CAS  PubMed  Google Scholar 

  • Chen HH, Glockner JF, Schirger JA, Cataliotti A, Redfield MM, Burnett JC Jr (2012a) Novel protein therapeutics for systolic heart failure: chronic subcutaneous B-type natriuretic peptide. J Am Coll Cardiol 60:2305–2312

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Chen W et al (2012b) Atrial natriuretic peptide enhances microvascular albumin permeability by the caveolae-mediated transcellular pathway. Cardiovasc Res 93:141–151

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Chen W et al (2013) Atrial natriuretic peptide-mediated inhibition of microcirculatory endothelial Ca2+ and permeability response to histamine involves cGMP-dependent protein kinase I and TRPC6 channels. Arterioscler Thromb Vasc Biol 33:2121–2129

    Article  CAS  PubMed  Google Scholar 

  • Coletta C et al (2012) Hydrogen sulfide and nitric oxide are mutually dependent in the regulation of angiogenesis and endothelium-dependent vasorelaxation. Proc Natl Acad Sci U S A 109:9161–9166

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Derbyshire ER, Marletta MA (2012) Structure and regulation of soluble guanylate cyclase. Annu Rev Biochem 81:533–559

    Article  CAS  PubMed  Google Scholar 

  • Ehret GB et al (2011) Genetic variants in novel pathways influence blood pressure and cardiovascular disease risk. Nature 478:103–109

    Article  CAS  PubMed  Google Scholar 

  • Erdmann J et al (2013) Dysfunctional nitric oxide signalling increases risk of myocardial infarction. Nature 504:432–436

    Article  CAS  PubMed  Google Scholar 

  • Frontini A, Cinti S (2010) Distribution and development of brown adipocytes in the murine and human adipose organ. Cell 11:253–256

    CAS  Google Scholar 

  • Ghofrani HA et al (2013a) Riociguat for the treatment of chronic thromboembolic pulmonary hypertension. N Engl J Med 369:319–329

    Article  CAS  PubMed  Google Scholar 

  • Ghofrani HA et al (2013b) Riociguat for the treatment of pulmonary arterial hypertension. N Engl J Med 369:330–340

    Article  CAS  PubMed  Google Scholar 

  • Ghosh A, Stuehr DJ (2012) Soluble guanylyl cyclase requires heat shock protein 90 for heme insertion during maturation of the NO-active enzyme. Proc Natl Acad Sci U S A 109:12998–13003

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Gotz KR et al (2014) Transgenic mice for real-time visualization of cGMP in intact adult cardiomyocytes. Circ Res 114:1235–1245

    Article  PubMed  Google Scholar 

  • Haas B et al (2009) Protein kinase g controls brown fat cell differentiation and mitochondrial biogenesis. Sci Signal 2:ra78

    Article  PubMed  Google Scholar 

  • Hawkridge AM, Heublein DM, Bergen HR 3rd, Cataliotti A, Burnett JC Jr, Muddiman DC (2005) Quantitative mass spectral evidence for the absence of circulating brain natriuretic peptide (BNP-32) in severe human heart failure. Proc Natl Acad Sci U S A 102:17442–17447

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Heckler EJ, Crassous PA, Baskaran P, Beuve A (2013) Protein disulfide-isomerase interacts with soluble guanylyl cyclase via a redox-based mechanism and modulates its activity. Biochem J 452:161–169

    CAS  PubMed Central  PubMed  Google Scholar 

  • Jaumann M et al (2012) cGMP-Prkg1 signaling and Pde5 inhibition shelter cochlear hair cells and hearing function. Nat Med 18:252–259

    Article  CAS  PubMed  Google Scholar 

  • Kajimura S, Saito M (2013) A new era in brown adipose tissue biology: molecular control of brown fat development and energy homeostasis. Annu Rev Physiol 76:225–249

    Article  PubMed  Google Scholar 

  • Klein S et al (2013) Interstitial cells of Cajal integrate excitatory and inhibitory neurotransmission with intestinal slow-wave activity. Nat Commun 4:1630

    Article  PubMed  Google Scholar 

  • Kumazoe M et al (2012) 67-kDa laminin receptor increases cGMP to induce cancer-selective apoptosis. J Clin Invest 123:787–799

    Google Scholar 

  • Lee CY, Chen HH, Lisy O, Swan S, Cannon C, Lieu HD, Burnett JC Jr (2009) Pharmacodynamics of a novel designer natriuretic peptide, CD-NP, in a first-in-human clinical trial in healthy subjects. J Clin Pharmacol 49:668–673

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Li P et al (2007) Guanylyl cyclase C suppresses intestinal tumorigenesis by restricting proliferation and maintaining genomic integrity. Gastroenterology 133:599–607

    Article  CAS  PubMed  Google Scholar 

  • Lies B, Groneberg D, Friebe A (2013) Correlation of cellular expression with function of NO-sensitive guanylyl cyclase in the murine lower urinary tract. J Physiol 591:5365–5375

    Article  CAS  PubMed  Google Scholar 

  • Liu N, Xu Y, Hossain S, Huang N, Coursolle D, Gralnick JA, Boon EM (2012) Nitric oxide regulation of cyclic di-GMP synthesis and hydrolysis in Shewanella woodyi. Biochemistry 51:2087–2099

    Article  CAS  PubMed  Google Scholar 

  • Lukowski R, Rybalkin SD, Loga F, Leiss V, Beavo JA, Hofmann F (2010) Cardiac hypertrophy is not amplified by deletion of cGMP-dependent protein kinase I in cardiomyocytes. Proc Natl Acad Sci U S A 107:5646–5651

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Mitrovic V, Jovanovic A, Lehinant S (2011) Soluble guanylate cyclase modulators in heart failure. Curr Heart Fail Rep 8:38–44

    Article  CAS  PubMed  Google Scholar 

  • Mitschke MM et al (2013) Increased cGMP promotes healthy expansion and browning of white adipose tissue. FASEB J 2013:9

    Google Scholar 

  • Mittendorf J et al (2009) Discovery of riociguat (BAY 63–2521): a potent, oral stimulator of soluble guanylate cyclase for the treatment of pulmonary hypertension. ChemMedChem 4:853–865

    Article  CAS  PubMed  Google Scholar 

  • Nakagawa Y et al (2014) The effects of super-flux (high performance) dialyzer on plasma glycosylated pro-B-type natriuretic peptide (proBNP) and glycosylated N-terminal proBNP in end-stage renal disease patients on dialysis. PLoS One 9:e92314

    Article  PubMed Central  PubMed  Google Scholar 

  • Nedergaard J, Cannon B (2010) The changed metabolic world with human brown adipose tissue: therapeutic visions. Cell Metab 11:268–272

    Article  CAS  PubMed  Google Scholar 

  • Newton-Cheh C et al (2009) Association of common variants in NPPA and NPPB with circulating natriuretic peptides and blood pressure. Nat Genet 41:348–353

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Pfeifer A, Kilic A, Hoffmann LS (2013) Regulation of metabolism by cGMP. Pharmacol Ther 140:81–91

    Article  CAS  PubMed  Google Scholar 

  • Prysyazhna O, Rudyk O, Eaton P (2012) Single atom substitution in mouse protein kinase G eliminates oxidant sensing to cause hypertension. Nat Med 18:286–290

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Rangaswami H et al (2010) Cyclic GMP and protein kinase G control a Src-containing mechanosome in osteoblasts. Sci Signal 3:2001423

    Article  Google Scholar 

  • Redfield MM et al (2013) Effect of phosphodiesterase-5 inhibition on exercise capacity and clinical status in heart failure with preserved ejection fraction: a randomized clinical trial. JAMA 309:1268–1277

    Article  CAS  PubMed  Google Scholar 

  • Robinson JW, Potter LR (2012) Guanylyl cyclases A and B are asymmetric dimers that are allosterically activated by ATP binding to the catalytic domain. Sci Signal 5:2003253

    Article  CAS  Google Scholar 

  • Rose RA (2010) CD-NP, a chimeric natriuretic peptide for the treatment of heart failure. Curr 11:349–356

    CAS  Google Scholar 

  • Rudyk O, Prysyazhna O, Burgoyne JR, Eaton P (2012) Nitroglycerin fails to lower blood pressure in redox-dead Cys42Ser PKG1alpha knock-in mouse. Circulation 126:287–295

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Rudyk O, Phinikaridou A, Prysyazhna O, Burgoyne JR, Botnar RM, Eaton P (2013) Protein kinase G oxidation is a major cause of injury during sepsis. Proc Natl Acad Sci U S A 110:9909–9913

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Salvi E et al (2012) Genomewide association study using a high-density single nucleotide polymorphism array and case–control design identifies a novel essential hypertension susceptibility locus in the promoter region of endothelial NO synthase. Hypertension 59:248–255

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Stasch JP, Pacher P, Evgenov OV (2011) Soluble guanylate cyclase as an emerging therapeutic target in cardiopulmonary disease. Circulation 123:2263–2273

    Article  PubMed Central  PubMed  Google Scholar 

  • Takimoto E et al (2005) Chronic inhibition of cyclic GMP phosphodiesterase 5A prevents and reverses cardiac hypertrophy. Nat Med 11:214–222

    Article  CAS  PubMed  Google Scholar 

  • Ter-Avetisyan G, Rathjen FG, Schmidt H (2014) Bifurcation of axons from cranial sensory neurons is disabled in the absence of Npr2-induced cGMP signaling. J Neurosci 34:737–747

    Article  CAS  PubMed  Google Scholar 

  • Thunemann M et al (2013) Transgenic mice for cGMP imaging. Circ Res 113:365–371

    Article  CAS  PubMed  Google Scholar 

  • Tsai EJ et al (2012) Pressure-overload-induced subcellular relocalization/oxidation of soluble guanylyl cyclase in the heart modulates enzyme stimulation. Circ Res 110:295–303

    Article  CAS  PubMed  Google Scholar 

  • Underbakke ES, Iavarone AT, Marletta MA (2013) Higher-order interactions bridge the nitric oxide receptor and catalytic domains of soluble guanylate cyclase. Proc Natl Acad Sci U S A 110:6777–6782

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Valentino MA et al (2011) A uroguanylin-GUCY2C endocrine axis regulates feeding in mice. J Clin Invest 121:3578–3588

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • van Heerebeek L et al (2012) Low myocardial protein kinase G activity in heart failure with preserved ejection fraction. Circulation 126:830–839

    Article  PubMed  Google Scholar 

  • Yamada-Goto N et al (2013) Intracerebroventricular administration of C-type natriuretic peptide suppresses food intake via activation of the melanocortin system in mice. Diabetes 62:1500–1504

    Article  CAS  PubMed Central  PubMed  Google Scholar 

Download references

Acknowledgments

We thank the organizers of cGMP 2013 John Burnett, Rochester, USA; Franz Hofmann, München, Germany; Harald Schmidt, Maastricht, The Netherlands; Johannes-Peter Stasch, Wuppertal, Germany; and Kazuwa Nakao, Kyoto, Japan, for their support in the summary of this meeting report.

Author information

Authors and Affiliations

  1. Institute of Pharmacology and Toxicology, Biomedical Center, University of Bonn, Bonn, Germany

    Linda S. Hoffmann

  2. Division of Cardiovascular Diseases, Mayo Clinic, Rochester, MN, USA

    Horng H. Chen

Authors
  1. Linda S. Hoffmann
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Horng H. Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Linda S. Hoffmann.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Hoffmann, L.S., Chen, H.H. cGMP: transition from bench to bedside: a report of the 6th International Conference on cGMP Generators, Effectors and Therapeutic Implications. Naunyn-Schmiedeberg's Arch Pharmacol 387, 707–718 (2014). https://doi.org/10.1007/s00210-014-0999-8

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00210-014-0999-8

Keywords

Search

Navigation