Publications by authors named "Andreas Friebe"

66 Publications

THE CONCISE GUIDE TO PHARMACOLOGY 2021/22: Catalytic receptors.

Br J Pharmacol 2021 Oct;178 Suppl 1:S264-S312

Thomas Jefferson University, Philadelphia, USA.

The Concise Guide to PHARMACOLOGY 2021/22 is the fifth in this series of biennial publications. The Concise Guide provides concise overviews, mostly in tabular format, of the key properties of nearly 1900 human drug targets with an emphasis on selective pharmacology (where available), plus links to the open access knowledgebase source of drug targets and their ligands (www.guidetopharmacology.org), which provides more detailed views of target and ligand properties. Although the Concise Guide constitutes over 500 pages, the material presented is substantially reduced compared to information and links presented on the website. It provides a permanent, citable, point-in-time record that will survive database updates. The full contents of this section can be found at http://onlinelibrary.wiley.com/doi/bph.15541. Catalytic receptors are one of the six major pharmacological targets into which the Guide is divided, with the others being: G protein-coupled receptors, ion channels, nuclear hormone receptors, enzymes and transporters. These are presented with nomenclature guidance and summary information on the best available pharmacological tools, alongside key references and suggestions for further reading. The landscape format of the Concise Guide is designed to facilitate comparison of related targets from material contemporary to mid-2021, and supersedes data presented in the 2019/20, 2017/18, 2015/16 and 2013/14 Concise Guides and previous Guides to Receptors and Channels. It is produced in close conjunction with the Nomenclature and Standards Committee of the International Union of Basic and Clinical Pharmacology (NC-IUPHAR), therefore, providing official IUPHAR classification and nomenclature for human drug targets, where appropriate.
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http://dx.doi.org/10.1111/bph.15541DOI Listing
October 2021

Inflammation in the Human Periodontium Induces Downregulation of the α- and β-Subunits of the sGC in Cementoclasts.

Int J Mol Sci 2021 Jan 7;22(2). Epub 2021 Jan 7.

Department of Periodontology and Operative Dentistry, University Medical Center of the Johannes Gutenberg University Mainz, 55131 Mainz, Germany.

Nitric oxide (NO) binds to soluble guanylyl cyclase (sGC), activates it in a reduced oxidized heme iron state, and generates cyclic Guanosine Monophosphate (cGMP), which results in vasodilatation and inhibition of osteoclast activity. In inflammation, sGC is oxidized and becomes insensitive to NO. NO- and heme-independent activation of sGC requires protein expression of the α- and β-subunits. Inflammation of the periodontium induces the resorption of cementum by cementoclasts and the resorption of the alveolar bone by osteoclasts, which can lead to tooth loss. As the presence of sGC in cementoclasts is unknown, we investigated the α- and β-subunits of sGC in cementoclasts of healthy and inflamed human periodontium using double immunostaining for CD68 and cathepsin K and compared the findings with those of osteoclasts from the same sections. In comparison to cementoclasts in the healthy periodontium, cementoclasts under inflammatory conditions showed a decreased staining intensity for both α- and β-subunits of sGC, indicating reduced protein expression of these subunits. Therefore, pharmacological activation of sGC in inflamed periodontal tissues in an NO- and heme-independent manner could be considered as a new treatment strategy to inhibit cementum resorption.
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http://dx.doi.org/10.3390/ijms22020539DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7827426PMC
January 2021

NO-sensitive guanylyl cyclase in the lung.

Br J Pharmacol 2020 Dec 17. Epub 2020 Dec 17.

Physiological Institute, Julius Maximilian University of Würzburg, Würzburg, Germany.

In the late 1960s, several labatories identified guanylyl cyclase (GC) as the cGMP-producing enzyme. Subsequently, two different types of GC were described that differed in their cellular localization. Primarily found in the cytosol, nitric oxide (NO)-sensitive guanylyl cyclase (NO-GC) acts as receptor for the signalling molecule NO, in contrast the membrane-bound isoenzyme is activated by natriuretic peptides. The lung compared with other tissues exhibits the highest expression of NO-GC. The enzyme has been purified from lung for biochemical analysis. Although expressed in smooth muscle cells (SMCs) and in pericytes, the function of NO-GC in lung, especially in pericytes, is still not fully elucidated. However, pharmacological compounds that target NO-GC are available and have been implemented for the therapy of pulmonary arterial hypertension. In addition, NO-GC has been suggested as drug target for the therapy of asthma, acute respiratory distress syndrome and pulmonary fibrosis.
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http://dx.doi.org/10.1111/bph.15345DOI Listing
December 2020

β-Adrenoceptor redistribution impairs NO/cGMP/PDE2 signalling in failing cardiomyocytes.

Elife 2020 03 31;9. Epub 2020 Mar 31.

Myocardial Function, National Heart and Lung Institute, Imperial College London, ICTEM, Hammersmith Hospital, London, United Kingdom.

Cardiomyocyte β-adrenoceptors (β-ARs) coupled to soluble guanylyl cyclase (sGC)-dependent production of the second messenger 3',5'-cyclic guanosine monophosphate (cGMP) have been shown to protect from heart failure. However, the exact localization of these receptors to fine membrane structures and subcellular compartmentation of β-AR/cGMP signals underpinning this protection in health and disease remain elusive. Here, we used a Förster Resonance Energy Transfer (FRET)-based cGMP biosensor combined with scanning ion conductance microscopy (SICM) to show that functional β-ARs are mostly confined to the T-tubules of healthy rat cardiomyocytes. Heart failure, induced via myocardial infarction, causes a decrease of the cGMP levels generated by these receptors and a change of subcellular cGMP compartmentation. Furthermore, attenuated cGMP signals led to impaired phosphodiesterase two dependent negative cGMP-to-cAMP cross-talk. In conclusion, topographic and functional reorganization of the β-AR/cGMP signalosome happens in heart failure and should be considered when designing new therapies acting via this receptor.
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http://dx.doi.org/10.7554/eLife.52221DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7138611PMC
March 2020

cGMP: a unique 2nd messenger molecule - recent developments in cGMP research and development.

Naunyn Schmiedebergs Arch Pharmacol 2020 02 18;393(2):287-302. Epub 2019 Dec 18.

Institute of Pharmacology and Clinical Pharmacy, Goethe University, Max-von-Laue-Str. 9, D-60438, Frankfurt am Main, Germany.

Cyclic guanosine monophosphate (cGMP) is a unique second messenger molecule formed in different cell types and tissues. cGMP targets a variety of downstream effector molecules and, thus, elicits a very broad variety of cellular effects. Its production is triggered by stimulation of either soluble guanylyl cyclase (sGC) or particulate guanylyl cyclase (pGC); both enzymes exist in different isoforms. cGMP-induced effects are regulated by endogenous receptor ligands such as nitric oxide (NO) and natriuretic peptides (NPs). Depending on the distribution of sGC and pGC and the formation of ligands, this pathway regulates not only the cardiovascular system but also the kidney, lung, liver, and brain function; in addition, the cGMP pathway is involved in the pathogenesis of fibrosis, inflammation, or neurodegeneration and may also play a role in infectious diseases such as malaria. Moreover, new pharmacological approaches are being developed which target sGC- and pGC-dependent pathways for the treatment of various diseases. Therefore, it is of key interest to understand this pathway from scratch, beginning with the molecular basis of cGMP generation, the structure and function of both guanylyl cyclases and cGMP downstream targets; research efforts also focus on the subsequent signaling cascades, their potential crosstalk, and also the translational and, ultimately, the clinical implications of cGMP modulation. This review tries to summarize the contributions to the "9th International cGMP Conference on cGMP Generators, Effectors and Therapeutic Implications" held in Mainz in 2019. Presented data will be discussed and extended also in light of recent landmark findings and ongoing activities in the field of preclinical and clinical cGMP research.
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http://dx.doi.org/10.1007/s00210-019-01779-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7260148PMC
February 2020

Gastrointestinal dysfunction in autism displayed by altered motility and achalasia in mice.

Proc Natl Acad Sci U S A 2019 10 14;116(44):22237-22245. Epub 2019 Oct 14.

Department of Human Molecular Genetics, Institute of Human Genetics, University of Heidelberg, D-69120 Heidelberg, Germany;

Gastrointestinal dysfunctions in individuals with autism spectrum disorder are poorly understood, although they are common among this group of patients. haploinsufficiency is characterized by autistic behavior, language impairment, and intellectual disability, but feeding difficulties and gastrointestinal problems have also been reported. Whether these are primary impairments, the result of altered eating behavior, or side effects of psychotropic medication remains unclear. To address this question, we investigated mice reflecting haploinsufficiency. These animals show decreased body weight and altered feeding behavior with reduced food and water intake. A pronounced muscular atrophy was detected in the esophagus and colon, caused by reduced muscle cell proliferation. Nitric oxide-induced relaxation of the lower esophageal sphincter was impaired and achalasia was confirmed in vivo by manometry. Foxp1 targets (, , and ) identified in the brain were dysregulated in the adult esophagus. Total gastrointestinal transit was significantly prolonged due to impaired colonic contractility. Our results have uncovered a previously unknown dysfunction (achalasia and impaired gut motility) that explains the gastrointestinal disturbances in patients with FOXP1 syndrome, with potential wider relevance for autism.
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http://dx.doi.org/10.1073/pnas.1911429116DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6825283PMC
October 2019

Cell-specific effects of nitric oxide on the efficiency and frequency of long distance contractions in murine colon.

Neurogastroenterol Motil 2019 06 4;31(6):e13589. Epub 2019 Apr 4.

Physiologisches Institut, Universität Würzburg, Würzburg, Germany.

Background: Nitric oxide (NO) mediates inhibitory neurotransmission and is a critical component of neuronal programs that generate propulsive contractions. NO acts via its receptor NO-sensitive guanylyl cyclase (NO-GC) which is expressed in smooth muscle cells (SMC) and interstitial cells of Cajal (ICC). Organ bath studies with colonic rings from NO-GC knockout mice (GCKO) have indicated NO-GC to modulate spontaneous contractions. The cell-specific effects of NO-GC on the dominant pan-colonic propulsive contraction, the long distance contractions (LDCs), of whole colon preparations have not yet been described.

Methods: Contractions of whole colon preparations from wild type (WT), global, and cell-specific GCKO were recorded. After transformation into spatiotemporal maps, motility patterns were analyzed. Simultaneous perfusion of the colon enabled the correlation of outflow with LDCs to analyze contraction efficiency.

Key Results: Deletion of NO-GC in both ICC and SMC (ie, in GCKO and SMC/ICC-GCKO) caused loss of typical LDC activity and instead generated high-frequency LDC-like contractions with inefficient propulsive activity. Frequency was also increased in WT, SMC-GCKO, and ICC-GCKO colon in the presence of L-NAME to block neuronal NO synthase. LDC efficiency was dependent on NO-GC in SMC as it was reduced in GCKO, SMC-GCKO, and ICC/SMC-GCKO colon; LDC efficiency was decreased in all genotypes in the presence of L-NAME.

Conclusions And Inferences: NO/cGMP signaling is critical for normal peristaltic movements; as NO-GC in both SMC and ICC is essential, both cell types appear to work in synchrony. The efficiency of contractions to expel fluid is particularly influenced by NO-GC in SMC.
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http://dx.doi.org/10.1111/nmo.13589DOI Listing
June 2019

Publisher Correction: A shear-dependent NO-cGMP-cGKI cascade in platelets acts as an auto-regulatory brake of thrombosis.

Nat Commun 2018 11 20;9(1):4969. Epub 2018 Nov 20.

Interfakultäres Institut für Biochemie, University of Tübingen, 72076, Tübingen, Germany.

The original version of this Article contained an error in the description of Supplementary Movie 4, in which the final sentence was inadvertently truncated. The HTML has been updated to include a corrected version of the 'Description of Additional Supplementary Files' file.
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http://dx.doi.org/10.1038/s41467-018-07409-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6244154PMC
November 2018

Distinct functions of soluble guanylyl cyclase isoforms NO-GC1 and NO-GC2 in inflammatory and neuropathic pain processing.

Pain 2019 Mar;160(3):607-618

Pharmakologisches Institut für Naturwissenschaftler, Goethe-Universität, Frankfurt am Main, Germany.

A large body of evidence indicates that nitric oxide (NO)/cGMP signaling essentially contributes to the processing of chronic pain. In general, NO-induced cGMP formation is catalyzed by 2 isoforms of guanylyl cyclase, NO-sensitive guanylyl cyclase 1 (NO-GC1) and 2 (NO-GC2). However, the specific functions of the 2 isoforms in pain processing remain elusive. Here, we investigated the distribution of NO-GC1 and NO-GC2 in the spinal cord and dorsal root ganglia, and we characterized the behavior of mice lacking either isoform in animal models of pain. Using immunohistochemistry and in situ hybridization, we demonstrate that both isoforms are localized to interneurons in the spinal dorsal horn with NO-GC1 being enriched in inhibitory interneurons. In dorsal root ganglia, the distribution of NO-GC1 and NO-GC2 is restricted to non-neuronal cells with NO-GC2 being the major isoform in satellite glial cells. Mice lacking NO-GC1 demonstrated reduced hypersensitivity in models of neuropathic pain, whereas their behavior in models of inflammatory pain was normal. By contrast, mice lacking NO-GC2 exhibited increased hypersensitivity in models of inflammatory pain, but their neuropathic pain behavior was unaltered. Cre-mediated deletion of NO-GC1 or NO-GC2 in spinal dorsal horn neurons recapitulated the behavioral phenotypes observed in the global knockout. Together, these results indicate that cGMP produced by NO-GC1 or NO-GC2 in spinal dorsal horn neurons exert distinct, and partly opposing, functions in chronic pain processing.
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http://dx.doi.org/10.1097/j.pain.0000000000001440DOI Listing
March 2019

A shear-dependent NO-cGMP-cGKI cascade in platelets acts as an auto-regulatory brake of thrombosis.

Nat Commun 2018 10 16;9(1):4301. Epub 2018 Oct 16.

Interfakultäres Institut für Biochemie, University of Tübingen, 72076, Tübingen, Germany.

Mechanisms that limit thrombosis are poorly defined. One of the few known endogenous platelet inhibitors is nitric oxide (NO). NO activates NO sensitive guanylyl cyclase (NO-GC) in platelets, resulting in an increase of cyclic guanosine monophosphate (cGMP). Here we show, using cGMP sensor mice to study spatiotemporal dynamics of platelet cGMP, that NO-induced cGMP production in pre-activated platelets is strongly shear-dependent. We delineate a new mode of platelet-inhibitory mechanotransduction via shear-activated NO-GC followed by cGMP synthesis, activation of cGMP-dependent protein kinase I (cGKI), and suppression of Ca signaling. Correlative profiling of cGMP dynamics and thrombus formation in vivo indicates that high cGMP concentrations in shear-exposed platelets at the thrombus periphery limit thrombosis, primarily through facilitation of thrombus dissolution. We propose that an increase in shear stress during thrombus growth activates the NO-cGMP-cGKI pathway, which acts as an auto-regulatory brake to prevent vessel occlusion, while preserving wound closure under low shear.
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http://dx.doi.org/10.1038/s41467-018-06638-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6191445PMC
October 2018

NO-GC in cells 'off the beaten track'.

Nitric Oxide 2018 07 4;77:12-18. Epub 2018 Apr 4.

Physiologisches Institut, Universität Würzburg, Würzburg, Germany.

Nitric oxide-sensitive guanylyl cyclase (NO-GC) has been shown to regulate a plethora of different functions in the body. These include, among many others, the fine-tuning of vascular tone, platelet reactivity and gastrointestinal motility. Evidence for the participation of NO-GC in these functions has been obtained from various species including humans, rodents, as well as insects. Clearly, individual cell types that express NO-GC contribute differentially to organ-specific NO/cGMP signaling in the body. Hence, identification of NO-GC-expressing cells and their individual involvement in NO/cGMP signaling constituted the focus of many studies over the last 40 years. Probably most information has been obtained from vascular smooth muscle cells and platelets, in which NO-GC is known to induce relaxation and inhibition of aggregation, respectively. Many other cell types that express the enzyme have been linked to certain functions, e.g. cardiomyocyte/inotropy or gastrointestinal smooth muscle cells/motility. However, in some cell types, e.g. myofibroblasts or pericytes, NO-GC expression is evident but individual functions of NO/cGMP signaling have yet to be assigned, whereas in other cell types, e.g. in erythrocytes, expression and role of NO-GC is still a matter of debate. This review discusses the current knowledge on 'less popular' cell types that express NO-GC (pericytes, myofibroblasts, cardiomyocytes, adipocytes, interstitial cells of Cajal, fibroblast-like cells and blood cells) and outlines possible further functions in cell types that have not gained strong attention so far.
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http://dx.doi.org/10.1016/j.niox.2018.03.020DOI Listing
July 2018

Cardioprotection by ischemic postconditioning and cyclic guanosine monophosphate-elevating agents involves cardiomyocyte nitric oxide-sensitive guanylyl cyclase.

Cardiovasc Res 2018 05;114(6):822-829

Department of Pharmacology, Toxicology and Clinical Pharmacy, Institute of Pharmacy, University of Tübingen, 72076 Tübingen, Germany.

Aims: It has been suggested that the nitric oxide-sensitive guanylyl cyclase (NO-GC)/cyclic guanosine monophosphate (cGMP)-dependent signalling pathway affords protection against cardiac damage during acute myocardial infarction (AMI). It is, however, not clear whether the NO-GC/cGMP system confers its favourable effects through a mechanism located in cardiomyocytes (CMs). The aim of this study was to evaluate the infarct-limiting effects of the endogenous NO-GC in CMs in vivo.

Methods And Results: Ischemia/reperfusion (I/R) injury was evaluated in mice with a CM-specific deletion of NO-GC (CM NO-GC KO) and in control siblings (CM NO-GC CTR) subjected to an in vivo model of AMI. Lack of CM NO-GC resulted in a mild increase in blood pressure but did not affect basal infarct sizes after I/R. Ischemic postconditioning (iPost), administration of the phosphodiesterase-5 inhibitors sildenafil and tadalafil as well as the NO-GC activator cinaciguat significantly reduced the amount of infarction in control mice but not in CM NO-GC KO littermates. Interestingly, NS11021, an opener of the large-conductance and Ca2+-activated potassium channel (BK), an important downstream effector of cGMP/cGKI in the cardiovascular system, protects I/R-exposed hearts of CM NO-GC proficient and deficient mice.

Conclusions: These findings demonstrate an important role of CM NO-GC for the cardioprotective signalling following AMI in vivo. CM NO-GC function is essential for the beneficial effects on infarct size elicited by iPost and pharmacological elevation of cGMP; however, lack of CM NO-GC does not seem to disrupt the cardioprotection mediated by the BK opener NS11021.
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http://dx.doi.org/10.1093/cvr/cvy039DOI Listing
May 2018

Correction to: Meeting report of the 8 International Conference on "cGMP BcGMP: generators, effectors, and therapeutic implications" at Bamberg, Germany, from June 23 to 25, 2017.

Naunyn Schmiedebergs Arch Pharmacol 2018 03;391(3):347

Institute of Pharmacology, College of Pharmacy, Goethe University, Max-von-Laue-Str. 9, 60438, Frankfurt, Germany.

The article "Meeting report of the 8 International Conference on "cGMP BcGMP: generators, effectors, and therapeutic implications" at Bamberg, Germany, from June 23 to 25, 2017" was originally published Online First without open access. After publication in volume 390, issue 12, pages 1177-1188, the author decided to opt for Open Choice and to make the article an open access publication.
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http://dx.doi.org/10.1007/s00210-018-1472-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6828335PMC
March 2018

The IgCAM CLMP regulates expression of Connexin43 and Connexin45 in intestinal and ureteral smooth muscle contraction in mice.

Dis Model Mech 2018 02 22;11(2). Epub 2018 Feb 22.

Max-Delbrück-Center for Molecular Medicine, DE-13092 Berlin, Germany

CAR-like membrane protein (CLMP), an immunoglobulin cell adhesion molecule (IgCAM), has been implicated in congenital short-bowel syndrome in humans, a condition with high mortality for which there is currently no cure. We therefore studied the function of CLMP in a -deficient mouse model. Although we found that the levels of mRNAs encoding Connexin43 or Connexin45 were not or were only marginally affected, respectively, by deficiency, the absence of CLMP caused a severe reduction of both proteins in smooth muscle cells of the intestine and of Connexin43 in the ureter. Analysis of calcium signaling revealed a disordered cell-cell communication between smooth muscle cells, which in turn induced an impaired and uncoordinated motility of the intestine and the ureter. Consequently, insufficient transport of chyme and urine caused a fatal delay to thrive, a high rate of mortality, and provoked a severe hydronephrosis in CLMP knockouts. Neurotransmission and the capability of smooth muscle cells to contract in ring preparations of the intestine were not altered. Physical obstructions were not detectable and an overall normal histology in the intestine as well as in the ureter was observed, except for a slight hypertrophy of smooth muscle layers. Deletion of did not lead to a reduced length of the intestine as shown for the human gene but resulted in gut malrotations. In sum, the absence of CLMP caused functional obstructions in the intestinal tract and ureter by impaired peristaltic contractions most likely due to a lack of gap-junctional communication between smooth muscle cells.
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http://dx.doi.org/10.1242/dmm.032128DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5894946PMC
February 2018

Protein kinases G are essential downstream mediators of the antifibrotic effects of sGC stimulators.

Ann Rheum Dis 2018 03 8;77(3):459. Epub 2018 Jan 8.

Department of Internal Medicine III - Rheumatology and Immunology, Friedrich-Alexander-University Erlangen-Nürnberg (FAU), Universitätsklinikum Erlangen, Erlangen, Germany.

Objectives: Stimulators of soluble guanylate cyclase (sGC) are currently investigated in clinical trials for the treatment of fibrosis in systemic sclerosis (SSc). In this study, we aim to investigate the role of protein kinases G (PKG) as downstream mediators of sGC-cyclic guanosine monophosphate (cGMP) in SSc.

Methods: Mice with combined knockout of PKG1 and 2 were challenged with bleomycin and treated with the sGC stimulator BAY 41-2272. Fibroblasts were treated with BAY 41-2272 and with the PKG inhibitor KT 5823.

Results: PKG1 and 2 are upregulated in SSc in a transforming growth factor-β1 (TGFβ1)-dependent manner, as an attempt to compensate for the decreased signalling through the sGC-cGMP-PKG pathway. Inhibition or knockout of PKG1 and 2 abrogates the inhibitory effects of sGC stimulation on fibroblast activation in a SMAD-independent, but extracellular signal-regulated kinase (ERK)-dependent manner. In vivo, sGC stimulation fails to prevent bleomycin-induced fibrosis in PKG1 and 2 knockout mice.

Conclusions: Our data provide evidence that PKGs are essential mediators of the antifibrotic effects of sGC stimulators through interfering with non-canonical TGFβ signalling. TGFβ1 promotes its profibrotic effects through inhibition of sGC-cGMP-PKG signalling, sGC stimulation exerts its antifibrotic effects by inhibition of TGFβ1-induced ERK phosphorylation.
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http://dx.doi.org/10.1136/annrheumdis-2017-212489DOI Listing
March 2018

Phosphodiesterase 3A expression and activity in the murine vasculature is influenced by NO-sensitive guanylyl cyclase.

Pflugers Arch 2018 04 2;470(4):693-702. Epub 2018 Jan 2.

Physiologisches Institut I, Universität Würzburg, Röntgenring 9, 97070, Würzburg, Germany.

Phosphodiesterase 3 (PDE3) exists in two isoforms (PDE3A and PDE3B) and is known to act as cGMP-inhibited cAMP-degrading PDE. Therefore, PDE3 may likely be involved in the interaction between the two second messenger pathways. NO-sensitive guanylyl cyclase (NO-GC) is the most important cytosolic generator of cGMP. Here, we investigated the effect of NO-GC deletion on PDE3A-mediated signaling in animals lacking NO-GC either globally (GCKO) or specifically in smooth muscle cells (SMC-GCKO). PDE3A expression is detected in murine aortic smooth muscle, platelets, and heart tissue. Expression and activity of PDE3A in aortae from GCKO and SMC-GCKO mice was reduced by approx. 50% compared to that in control animals. PDE3A downregulation can be linked to the reduction in NO-GC and is not an effect of the increased blood pressure levels resulting from NO-GC deletion. Despite the different PDE3A expression levels, smooth muscle relaxation induced by forskolin to stimulate cAMP signaling was similar in all genotypes. Basal and forskolin-stimulated cAMP levels in aortic tissue were not different between KO and control strains. However, the potency of milrinone, a selective inhibitor of PDE3A, to induce relaxation was higher in aortae from GCKO and SMC-GCKO than that in aorta from control animals. These data were corroborated by the effect of milrinone in vivo, which led to an increase in systolic blood pressure in both KO strains but not in control mice. We conclude that NO-GC modulates PDE3A expression and activity in SMC in vivo conceivably to preserve functional cAMP signaling.
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http://dx.doi.org/10.1007/s00424-017-2106-8DOI Listing
April 2018

Meeting report of the 8 International Conference on cGMP "cGMP: generators, effectors, and therapeutic implications" at Bamberg, Germany, from June 23 to 25, 2017.

Naunyn Schmiedebergs Arch Pharmacol 2017 Dec 10;390(12):1177-1188. Epub 2017 Oct 10.

Institute of Pharmacology, College of Pharmacy, Goethe University, Max-von-Laue-Str. 9, 60438, Frankfurt, Germany.

Although the Nobel Prize for the discovery of nitric oxide (NO) dates back almost 20 years now, the knowledge about cGMP signaling is still constantly increasing. It looks even so that our understanding of the role of the soluble guanylyl cyclase (sGC) and particulate guanylyl cyclase (pGC) in health and disease is in many aspects at the beginning and far from being understood. This holds even true for the therapeutic impact of innovative drugs acting on both the NO/sGC and the pGC pathways. Since cGMP, as second messenger, is involved in the pathogenesis of numerous diseases within the cardiovascular, pulmonary, renal, and endocrine systems and also plays a role in neuronal, sensory, and tumor processes, drug applications might be quite broad. On the 8th International Conference on cGMP, held in Bamberg, Germany, world leading experts came together to discuss these topics. All aspects of cGMP research from the basic understanding of cGMP signaling to clinical applicability were discussed in depth. In addition, present and future therapeutic applications of cGMP-modulating pharmacotherapy were presented ( http://www.cyclicgmp.net/index.html ).
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http://dx.doi.org/10.1007/s00210-017-1429-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5783999PMC
December 2017

NO-Sensitive Guanylate Cyclase Isoforms NO-GC1 and NO-GC2 Contribute to Noise-Induced Inner Hair Cell Synaptopathy.

Mol Pharmacol 2017 10;92(4):375-388

Department of Otolaryngology, Head and Neck Surgery, Hearing Research Centre Tübingen, Molecular Physiology of Hearing, University of Tübingen, Tübingen (D.M., K.R., S.W., K.V., N.E., H.-S.G., U.Z., M.K., L.R.), Interfaculty Institute of Biochemistry, University of Tübingen, Tübingen (M.W., R.F.), Department of Pharmacology and Toxicology, University of Bochum, Bochum (E.M., D.K.), Bayer AG, Drug Discovery Pharma Research Centre Wuppertal, Wuppertal (P.S.), Department of Pharmacology, Toxicology and Clinical Pharmacy, Institute of Pharmacy, University of Tübingen, Tübingen (P.R.), and Department of Physiology, University of Würzburg, Würzburg (A.F.), Germany

Nitric oxide (NO) activates the NO-sensitive soluble guanylate cyclase (NO-GC, sGC) and triggers intracellular signaling pathways involving cGMP. For survival of cochlear hair cells and preservation of hearing, NO-mediated cascades have both protective and detrimental potential. Here we examine the cochlear function of mice lacking one of the two NO-sensitive guanylate cyclase isoforms [NO-GC1 knockout (KO) or NO-GC2 KO]. The deletion of NO-GC1 or NO-GC2 did not influence electromechanical outer hair cell (OHC) properties, as measured by distortion product otoacoustic emissions, neither before nor after noise exposure, nor were click- or noise-burst-evoked auditory brainstem response thresholds different from controls. Yet inner hair cell (IHC) ribbons and auditory nerve responses showed significantly less deterioration in NO-GC1 KO and NO-GC2 KO mice after noise exposure. Consistent with a selective role of NO-GC in IHCs, NO-GC 1 mRNA was found in isolated IHCs but not in OHCs. Using transgenic mice expressing the fluorescence resonance energy transfer-based cGMP biosensor cGi500, NO-induced elevation of cGMP was detected in real-time in IHCs but not in OHCs. Pharmacologic long-term treatment with a NO-GC stimulator altered auditory nerve responses but did not affect OHC function and hearing thresholds. Interestingly, NO-GC stimulation exacerbated the loss of auditory nerve response in aged animals but attenuated the loss in younger animals. We propose NO-GC2 and, to some degree, NO-GC1 as targets for early pharmacologic prevention of auditory fiber loss (synaptopathy). Both isoforms provide selective benefits for hearing function by maintaining the functional integrity of auditory nerve fibers in early life rather than at old age.
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http://dx.doi.org/10.1124/mol.117.108548DOI Listing
October 2017

Optical control of a receptor-linked guanylyl cyclase using a photoswitchable peptidic hormone.

Chem Sci 2017 Jun 19;8(6):4644-4653. Epub 2017 Apr 19.

Department of Chemistry and Center for Integrated Protein Science , LMU Munich , Butenandtstr. 5-13 , 81377 Munich , Germany . Email: ; Email:

The optical control over biological function with small photoswitchable molecules has gathered significant attention in the last decade. Herein, we describe the design and synthesis of a small library of photoswitchable peptidomimetics based upon human atrial natriuretic peptide (ANP), in which the photochromic amino acid [3-(3-aminomethyl)phenylazo]phenylacetic acid (AMPP) is incorporated into the peptide backbone. The endogeneous hormone ANP signals the natriuretic peptide receptor A (NPR-A) through raising intracellular cGMP concentrations, and is involved in blood pressure regulation and sodium homeostasis, as well as lipid metabolism and pancreatic function. The - and -isomers of one of our peptidomimetics, termed TOP271, exhibit a four-fold difference in NPR-A mediated cGMP synthesis . Despite this seemingly small difference, TOP271 enables large, optically-induced conformational changes and transforms the NPR-A into an endogenous photoswitch. Thus, application of TOP271 allows the reversible generation of cGMP using light and remote control can be afforded over vasoactivity in explanted murine aortic rings, as well as pancreatic beta cell function in islets of Langerhans. This study demonstrates the broad applicability of TOP271 to enzyme-dependent signalling processes, extends the toolbox of photoswitchable molecules to all classes of transmembrane receptors and utilizes photopharmacology to deduce receptor activation on a molecular level.
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http://dx.doi.org/10.1039/c6sc05044aDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5471452PMC
June 2017

The enteric nervous system is a potential autoimmune target in multiple sclerosis.

Acta Neuropathol 2017 08 15;134(2):281-295. Epub 2017 Jun 15.

Department of Anatomy and Cell Biology, University of Würzburg, Würzburg, Germany.

Multiple sclerosis (MS) is a chronic autoimmune disease of the central nervous system (CNS) in young adults that has serious negative socioeconomic effects. In addition to symptoms caused by CNS pathology, the majority of MS patients frequently exhibit gastrointestinal dysfunction, which was previously either explained by the presence of spinal cord lesions or not directly linked to the autoimmune etiology of the disease. Here, we studied the enteric nervous system (ENS) in a B cell- and antibody-dependent mouse model of MS by immunohistochemistry and electron microscopy at different stages of the disease. ENS degeneration was evident prior to the development of CNS lesions and the onset of neurological deficits in mice. The pathology was antibody mediated and caused a significant decrease in gastrointestinal motility, which was associated with ENS gliosis and neuronal loss. We identified autoantibodies against four potential target antigens derived from enteric glia and/or neurons by immunoprecipitation and mass spectrometry. Antibodies against three of the target antigens were also present in the plasma of MS patients as confirmed by ELISA. The analysis of human colon resectates provided evidence of gliosis and ENS degeneration in MS patients compared to non-MS controls. For the first time, this study establishes a pathomechanistic link between the well-established autoimmune attack on the CNS and ENS pathology in MS, which might provide a paradigm shift in our current understanding of the immunopathogenesis of the disease with broad diagnostic and therapeutic implications.
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http://dx.doi.org/10.1007/s00401-017-1742-6DOI Listing
August 2017

Integrative Control of Gastrointestinal Motility by Nitric Oxide.

Curr Med Chem 2016 ;23(24):2715-2735

Physiologisches Institut, Universität Würzburg, Röntgenring 9, 97070 Würzburg, Germany.

In the gastrointestinal (GI) tract, nitric oxide (NO) has been shown over the last 25 years to exert a prominent function as inhibitory neurotransmitter. Apart from the regulation of secretion and resorption, NO from nitrergic neurons has been demonstrated to be crucial for GI smooth muscle relaxation and motility. In fact, several human diseases such as achalasia, gastroparesis, slow transit constipation or Hirschsprung's disease may involve dysfunctional nitrergic signaling. Most of NO's effects as neurotransmitter are mediated by NO-sensitive guanylyl cyclase (NO-GC) and further transduced by cGMP-dependent mechanisms. In contrast to the vascular system where NO from the endothelium induces relaxation by acting on NO-GC solely in smooth muscle cells, GI tissues contain several different NO-GCexpressing cell types that include smooth muscle cells, interstitial cells of Cajal and fibroblast-like cells. Based on this diverse localization of the NO receptor, the exact pathway(s) leading to NO-induced relaxation are still unknown. Global and cell-specific knockout mouse strains have been generated that lack enzymes participating in nitrergic signaling. These animals have been helpful in examining the role of NO in smooth muscle of the GI tract. Here, we discuss the current knowledge on NO-mediated mechanisms in the relaxation of GI smooth muscle in stomach, small and large intestine including sphincters. Special focus is placed on the integration of nitrergic signals by specialized cell types within the gut smooth muscle layers.
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http://dx.doi.org/10.2174/0929867323666160812150907DOI Listing
February 2017

Erythrocytes do not activate purified and platelet soluble guanylate cyclases even in conditions favourable for NO synthesis.

Cell Commun Signal 2016 08 11;14(1):16. Epub 2016 Aug 11.

Center for Thrombosis and Hemostasis (CTH), University Medical Center Mainz, Mainz, Germany.

Background: Direct interaction between Red blood cells (RBCs) and platelets is known for a long time. The bleeding time is prolonged in anemic patients independent of their platelet count and could be corrected by transfusion of RBCs, which indicates that RBCs play an important role in hemostasis and platelet activation. However, in the last few years, opposing mechanisms of platelet inhibition by RBCs derived nitric oxide (NO) were proposed. The aim of our study was to identify whether RBCs could produce NO and activate soluble guanylate cyclase (sGC) in platelets.

Methods: To test whether RBCs could activate sGC under different conditions (whole blood, under hypoxia, or even loaded with NO), we used our well-established and highly sensitive models of NO-dependent sGC activation in platelets and activation of purified sGC. The activation of sGC was monitored by detecting the phosphorylation of Vasodilator Stimulated Phosphoprotein (VASP(S239)) by flow cytometry and Western blot. ANOVA followed by Bonferroni's test and Student's t-test were used as appropriate.

Results: We show that in the whole blood, RBCs prevent NO-mediated inhibition of ADP and TRAP6-induced platelet activation. Likewise, coincubation of RBCs with platelets results in strong inhibition of NO-induced sGC activation. Under hypoxic conditions, incubation of RBCs with NO donor leads to Hb-NO formation which inhibits sGC activation in platelets. Similarly, RBCs inhibit activation of purified sGC, even under conditions optimal for RBC-mediated generation of NO from nitrite.

Conclusions: All our experiments demonstrate that RBCs act as strong NO scavengers and prevent NO-mediated inhibition of activated platelets. In all tested conditions, RBCs were not able to activate platelet or purified sGC.
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http://dx.doi.org/10.1186/s12964-016-0139-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4982240PMC
August 2016

Stimulators of the soluble guanylyl cyclase: promising functional insights from rare coding atherosclerosis-related GUCY1A3 variants.

Basic Res Cardiol 2016 07 24;111(4):51. Epub 2016 Jun 24.

Klinik für Herz- und Kreislauferkrankungen, Deutsches Herzzentrum München, Technische Universität München, Lazarettstr. 36, 80636, Munich, Germany.

Stimulators of the soluble guanylyl cyclase (sGC) are emerging therapeutic agents in cardiovascular diseases. Genetic alterations of the GUCY1A3 gene, which encodes the α1 subunit of the sGC, are associated with coronary artery disease. Studies investigating sGC stimulators in subjects with CAD and carrying risk-related variants in sGC are, however, lacking. Here, we functionally investigate the impact of coding GUCY1A3 variants on sGC activity and the therapeutic potential of sGC stimulators in vitro. In addition to a known loss-of-function variant, eight coding variants in GUCY1A3 were cloned and expressed in HEK 293 cells. Protein levels and dimerization capability with the β1 subunit were analysed by immunoblotting and co-immunoprecipitation, respectively. All α1 variants found in MI patients dimerized with the β1 subunit. Protein levels were reduced by 72 % in one variant (p < 0.01). Enzymatic activity was analysed using cGMP radioimmunoassay after stimulation with a nitric oxide (NO) donor. Five variants displayed decreased cGMP production upon NO stimulation (p < 0.001). The addition of the sGC stimulator BAY 41-2272 increased cGMP formation in all of these variants (p < 0.01). Except for the variant leading to decreased protein level, cGMP amounts reached the wildtype NO-induced level after addition of BAY 41-2272. In conclusion, rare coding variants in GUCY1A3 lead to reduced cGMP formation which can be rescued by a sGC stimulator in vitro. These results might therefore represent the starting point for discovery of novel treatment strategies for patients at risk with coding GUCY1A3 variants.
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http://dx.doi.org/10.1007/s00395-016-0570-5DOI Listing
July 2016

Soluble guanylate cyclase as an alternative target for bronchodilator therapy in asthma.

Proc Natl Acad Sci U S A 2016 Apr 11;113(17):E2355-62. Epub 2016 Apr 11.

Department of Pathobiology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195;

Asthma is defined by airway inflammation and hyperresponsiveness, and contributes to morbidity and mortality worldwide. Although bronchodilation is a cornerstone of treatment, current bronchodilators become ineffective with worsening asthma severity. We investigated an alternative pathway that involves activating the airway smooth muscle enzyme, soluble guanylate cyclase (sGC). Activating sGC by its natural stimulant nitric oxide (NO), or by pharmacologic sGC agonists BAY 41-2272 and BAY 60-2770, triggered bronchodilation in normal human lung slices and in mouse airways. Both BAY 41-2272 and BAY 60-2770 reversed airway hyperresponsiveness in mice with allergic asthma and restored normal lung function. The sGC from mouse asthmatic lungs displayed three hallmarks of oxidative damage that render it NO-insensitive, and identical changes to sGC occurred in human lung slices or in human airway smooth muscle cells when given chronic NO exposure to mimic the high NO in asthmatic lung. Our findings show how allergic inflammation in asthma may impede NO-based bronchodilation, and reveal that pharmacologic sGC agonists can achieve bronchodilation despite this loss.
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http://dx.doi.org/10.1073/pnas.1524398113DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4855555PMC
April 2016

CrossTalk proposal: Interstitial cells are involved and physiologically important in neuromuscular transmission in the gut.

J Physiol 2016 Mar 3;594(6):1507-9. Epub 2016 Feb 3.

Physiologisches Institut, Universität Würzburg, Würzburg, Germany.

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http://dx.doi.org/10.1113/JP271600DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4739874PMC
March 2016

Rebuttal from Kenton M. Sanders, Sean M. Ward and Andreas Friebe.

J Physiol 2016 Mar 3;594(6):1515. Epub 2016 Feb 3.

Physiologisches Institut, Universität Würzburg, Würzburg, Germany.

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http://dx.doi.org/10.1113/JP271971DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4739873PMC
March 2016

From bedside to bench--meeting report of the 7th International Conference on cGMP "cGMP: generators, effectors and therapeutic implications" in Trier, Germany, from June 19th to 21st 2015.

Naunyn Schmiedebergs Arch Pharmacol 2015 Dec 20;388(12):1237-46. Epub 2015 Oct 20.

Institute of Pharmacology, Hannover Medical School, Carl-Neuberg-Str. 1, 30625, Hannover, Germany.

During the past decade, our knowledge on the physiology, pathophysiology, basic pharmacology, and clinical pharmacology of the second messenger (cGMP) has increased tremendously. It is now well-established that cGMP, generated by soluble and particulate guanylate cyclases, is highly compartmentalized in cells and regulates numerous body functions. New cGMP-regulated physiological functions include meiosis and temperature perception. cGMP is involved in the genesis of numerous pathologies including cardiovascular, pulmonary, endocrine, metabolic, neuropsychiatric, eye, and tumor diseases. Several new clinical uses of stimulators and activators of soluble guanylate cyclase and of phosphodiesterase inhibitors such as heart failure, kidney failure, cognitive disorders, obesity bronchial asthma, and osteoporosis are emerging. The combination of neprilysin inhibitors-enhancing stimulation of the particulate guanylate cyclase pathway by preventing natriuretic peptide degradation-with angiotensin AT1 receptor antagonists constitutes a novel promising strategy for heart failure treatment. The role of oxidative stress in cGMP signaling, application of cGMP sensors, and gene therapy for degenerative eye diseases are emerging topics. It is anticipated that cGMP research will further prosper over the next years and reach out into more and more basic and clinical disciplines.
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http://dx.doi.org/10.1007/s00210-015-1176-4DOI Listing
December 2015

Nitrergic signalling via interstitial cells of Cajal regulates motor activity in murine colon.

J Physiol 2015 Oct 21;593(20):4589-601. Epub 2015 Aug 21.

Physiologisches Institut, Universität Würzburg, Würzburg, Germany.

In the enteric nervous systems, NO is released from nitrergic neurons as a major inhibitory neurotransmitter. NO acts via NO-sensitive guanylyl cyclase (NO-GC), which is found in different gastrointestinal (GI) cell types including smooth muscle cells (SMCs) and interstitial cells of Cajal (ICC). The precise mechanism of nitrergic signalling through these two cell types to regulate colonic spontaneous contractions is not fully understood yet. In the present study we investigated the impact of endogenous and exogenous NO on colonic contractile motor activity using mice lacking nitric oxide-sensitive guanylyl cyclase (NO-GC) globally and specifically in SMCs and ICC. Longitudinal smooth muscle of proximal colon from wild-type (WT) and knockout (KO) mouse strains exhibited spontaneous contractile activity ex vivo. WT and smooth muscle-specific guanylyl cyclase knockout (SMC-GCKO) colon showed an arrhythmic contractile activity with varying amplitudes and frequencies. In contrast, colon from global and ICC-specific guanylyl cyclase knockout (ICC-GCKO) animals showed a regular contractile rhythm with constant duration and amplitude of the rhythmic contractions. Nerve blockade (tetrodotoxin) or specific blockade of NO signalling (L-NAME, ODQ) did not significantly affect contractions of GCKO and ICC-GCKO colon whereas the arrhythmic contractile patterns of WT and SMC-GCKO colon were transformed into uniform motor patterns. In contrast, the response to electric field-stimulated neuronal NO release was similar in SMC-GCKO and global GCKO. In conclusion, our results indicate that basal enteric NO release acts via myenteric ICC to influence the generation of spontaneous contractions whereas the effects of elevated endogenous NO are mediated by SMCs in the murine proximal colon.
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http://dx.doi.org/10.1113/JP270511DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4606533PMC
October 2015

Sildenafil Does Not Prevent Heart Hypertrophy and Fibrosis Induced by Cardiomyocyte Angiotensin II Type 1 Receptor Signaling.

J Pharmacol Exp Ther 2015 Sep 8;354(3):406-16. Epub 2015 Jul 8.

Department of Pharmacology, Toxicology and Clinical Pharmacy, Institute of Pharmacy, University of Tübingen, Tübingen, Germany (J.S., V.S., N.B., R.L.); Institute of Experimental Cardiovascular Research, University Medical Center Hamburg-Eppendorf, Hamburg, Germany (H.S., V.O.N.); Physiologisches Institut I, Universität Würzburg, Würzburg, Germany (S.D., A.F.); Institut für Pharmakologie und Toxikologie, Ruhr-Universität Bochum, Bochum, Germany (M.R.); Internal Medicine III, Cardiology and Cardiovascular Medicine, University Hospital Tübingen, Tübingen, Germany (M.G.); Laboratory of Cardiac Development and Differentiation, Department of Biochemistry, Microbiology, and Immunology, University of Ottawa, Ottawa, Ontario, Canada (M.N.); and Institut de Recherches Cliniques de Montréal, Montreal, Quebec, Canada (M.N.)

Analyses of several mouse models imply that the phosphodiesterase 5 (PDE5) inhibitor sildenafil (SIL), via increasing cGMP, affords protection against angiotensin II (Ang II)-stimulated cardiac remodeling. However, it is unclear which cell types are involved in these beneficial effects, because Ang II may exert its adverse effects by modulating multiple renovascular and cardiac functions via Ang II type 1 receptors (AT1Rs). To test the hypothesis that SIL/cGMP inhibit cardiac stress provoked by amplified Ang II/AT1R directly in cardiomyocytes (CMs), we studied transgenic mice with CM-specific overexpression of the AT1R under the control of the α-myosin heavy chain promoter (αMHC-AT1R(tg/+)). The extent of cardiac growth was assessed in the absence or presence of SIL and defined by referring changes in heart weight to body weight or tibia length. Hypertrophic marker genes, extracellular matrix-regulating factors, and expression patterns of fibrosis markers were examined in αMHC-AT1R(tg/+) ventricles (with or without SIL) and corroborated by investigating different components of the natriuretic peptide/PDE5/cGMP pathway as well as cardiac functions. cGMP levels in heart lysates and intact CMs were measured by competitive immunoassays and Förster resonance energy transfer. We found higher cardiac and CM cGMP levels and upregulation of the cGMP-dependent protein kinase type I with AT1R overexpression. However, even a prolonged SIL treatment regimen did not limit the progressive CM growth, fibrosis, or decline in cardiac functions in the αMHC-AT1R(tg/+) model, suggesting that SIL does not interfere with the pathogenic actions of amplified AT1R signaling in CMs. Hence, the cardiac/noncardiac cells involved in the cross-talk between SIL-sensitive PDE activity and Ang II/AT1R still need to be identified.
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http://dx.doi.org/10.1124/jpet.115.226092DOI Listing
September 2015

Stimulation of soluble guanylyl cyclase protects against obesity by recruiting brown adipose tissue.

Nat Commun 2015 May 26;6:7235. Epub 2015 May 26.

Institute of Pharmacology and Toxicology, University Hospital Bonn, University of Bonn, Bonn D-53105, Germany.

Obesity is characterized by a positive energy balance and expansion of white adipose tissue (WAT). In contrast, brown adipose tissue (BAT) combusts energy to produce heat. Here we show that a small molecule stimulator (BAY 41-8543) of soluble guanylyl cyclase (sGC), which produces the second messenger cyclic GMP (cGMP), protects against diet-induced weight gain, induces weight loss in established obesity, and also improves the diabetic phenotype. Mechanistically, the haeme-dependent sGC stimulator BAY 41-8543 enhances lipid uptake into BAT and increases whole-body energy expenditure, whereas ablation of the haeme-containing β1-subunit of sGC severely impairs BAT function. Notably, the sGC stimulator enhances differentiation of human brown adipocytes as well as induces 'browning' of primary white adipocytes. Taken together, our data suggest that sGC is a potential pharmacological target for the treatment of obesity and its comorbidities.
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http://dx.doi.org/10.1038/ncomms8235DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4455111PMC
May 2015
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