Editorial

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Open AccessEditorial

Editorial of the Special Issue: cGMP-Signaling in Cells and Tissues: Molecular, Functional and Pharmacological Aspects

by Jens Schlossmann

Int. J. Mol. Sci. 2022, 23(12), 6482; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23126482 - 10 Jun 2022

Cited by 1 | Viewed by 971

Several important and novel aspects regarding signaling by cGMP were reported in the various publications of this Special Issue [...] Full article

(This article belongs to the Special Issue cGMP-Signaling in Cells and Tissues: Molecular, Functional, and Pharmacological Aspects)

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24 pages, 3265 KiB

Open AccessArticle

Cyclic GMP-Dependent Regulation of Vascular Tone and Blood Pressure Involves Cysteine-Rich LIM-Only Protein 4 (CRP4)

by Natalie Längst, Julia Adler, Olga Schweigert, Felicia Kleusberg, Melanie Cruz Santos, Amelie Knauer, Matthias Sausbier, Tanja Zeller, Peter Ruth and Robert Lukowski

Int. J. Mol. Sci. 2021, 22(18), 9925; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22189925 - 14 Sep 2021

Cited by 2 | Viewed by 2218

Abstract

The cysteine-rich LIM-only protein 4 (CRP4), a LIM-domain and zinc finger containing adapter protein, has been implicated as a downstream effector of the second messenger 3′,5′-cyclic guanosine monophosphate (cGMP) pathway in multiple cell types, including vascular smooth muscle cells (VSMCs). VSMCs and nitric [...] Read more.

The cysteine-rich LIM-only protein 4 (CRP4), a LIM-domain and zinc finger containing adapter protein, has been implicated as a downstream effector of the second messenger 3′,5′-cyclic guanosine monophosphate (cGMP) pathway in multiple cell types, including vascular smooth muscle cells (VSMCs). VSMCs and nitric oxide (NO)-induced cGMP signaling through cGMP-dependent protein kinase type I (cGKI) play fundamental roles in the physiological regulation of vascular tone and arterial blood pressure (BP). However, it remains unclear whether the vasorelaxant actions attributed to the NO/cGMP axis require CRP4. This study uses mice with a targeted deletion of the CRP4 gene (CRP4 KO) to elucidate whether cGMP-elevating agents, which are well known for their vasorelaxant properties, affect vessel tone, and thus, BP through CRP4. Cinaciguat, a NO- and heme-independent activator of the NO-sensitive (soluble) guanylyl cyclase (NO-GC) and NO-releasing agents, relaxed both CRP4-proficient and -deficient aortic ring segments pre-contracted with prostaglandin F2α. However, the magnitude of relaxation was slightly, but significantly, increased in vessels lacking CRP4. Accordingly, CRP4 KO mice presented with hypotonia at baseline, as well as a greater drop in systolic BP in response to the acute administration of cinaciguat, sodium nitroprusside, and carbachol. Mechanistically, loss of CRP4 in VSMCs reduced the Ca²⁺-sensitivity of the contractile apparatus, possibly involving regulatory proteins, such as myosin phosphatase targeting subunit 1 (MYPT1) and the regulatory light chain of myosin (RLC). In conclusion, the present findings confirm that the adapter protein CRP4 interacts with the NO-GC/cGMP/cGKI pathway in the vasculature. CRP4 seems to be part of a negative feedback loop that eventually fine-tunes the NO-GC/cGMP axis in VSMCs to increase myofilament Ca²⁺ desensitization and thereby the maximal vasorelaxant effects attained by (selected) cGMP-elevating agents. Full article

(This article belongs to the Special Issue cGMP-Signaling in Cells and Tissues: Molecular, Functional, and Pharmacological Aspects)

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19 pages, 42339 KiB

Open AccessArticle

Assessing the Use of the sGC Stimulator BAY-747, as a Potential Treatment for Duchenne Muscular Dystrophy

by Shalini Murali Krishnan, Johannes Nordlohne, Lisa Dietz, Alexandros Vakalopoulos, Petra Haning, Elke Hartmann, Roland Seifert, Jörg Hüser, Ilka Mathar and Peter Sandner

Int. J. Mol. Sci. 2021, 22(15), 8016; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22158016 - 27 Jul 2021

Cited by 3 | Viewed by 2476

Abstract

Duchenne muscular dystrophy (DMD) is a severe and progressive muscle wasting disorder, affecting one in 3500 to 5000 boys worldwide. The NO-sGC-cGMP pathway plays an important role in skeletal muscle function, primarily by improving blood flow and oxygen supply to the muscles during [...] Read more.

Duchenne muscular dystrophy (DMD) is a severe and progressive muscle wasting disorder, affecting one in 3500 to 5000 boys worldwide. The NO-sGC-cGMP pathway plays an important role in skeletal muscle function, primarily by improving blood flow and oxygen supply to the muscles during exercise. In fact, PDE5 inhibitors have previously been investigated as a potential therapy for DMD, however, a large-scale Phase III clinical trial did not meet its primary endpoint. Since the efficacy of PDE5i is dependent on sufficient endogenous NO production, which might be impaired in DMD, we investigated if NO-independent sGC stimulators, could have therapeutic benefits in a mouse model of DMD. Male mdx/mTR^G2 mice aged six weeks were given food supplemented with the sGC stimulator, BAY-747 (150 mg/kg of food) or food alone (untreated) ad libitum for 16 weeks. Untreated C57BL6/J mice were used as wild type (WT) controls. Assessments of the four-limb hang, grip strength, running wheel and serum creatine kinase (CK) levels showed that mdx/mTR^G2 mice had significantly reduced skeletal muscle function and severe muscle damage compared to WT mice. Treatment with BAY-747 improved grip strength and running speed, and these mice also had reduced CK levels compared to untreated mdx/mTR^G2 mice. We also observed increased inflammation and fibrosis in the skeletal muscle of mdx/mTR^G2 mice compared to WT. While gene expression of pro-inflammatory cytokines and some pro-fibrotic markers in the skeletal muscle was reduced following BAY-747 treatment, there was no reduction in infiltration of myeloid immune cells nor collagen deposition. In conclusion, treatment with BAY-747 significantly improves several functional and pathological parameters of the skeletal muscle in mdx/mTR^G2 mice. However, the effect size was moderate and therefore, more studies are needed to fully understand the potential treatment benefit of sGC stimulators in DMD. Full article

(This article belongs to the Special Issue cGMP-Signaling in Cells and Tissues: Molecular, Functional, and Pharmacological Aspects)

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20 pages, 5271 KiB

Open AccessArticle

Loss of PKGIβ/IRAG1 Signaling Causes Anemia-Associated Splenomegaly

by Michael Majer, Sally Prueschenk and Jens Schlossmann

Int. J. Mol. Sci. 2021, 22(11), 5458; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22115458 - 21 May 2021

Cited by 4 | Viewed by 2332

Abstract

Inositol 1,4,5-triphosphate receptor-associated cGMP kinase substrate 1 (IRAG1) is a substrate protein of the NO/cGMP-signaling pathway and forms a ternary complex with the cGMP-dependent protein kinase Iβ (PKGIβ) and the inositol triphosphate receptor I (IP₃R-I). Functional studies about IRAG1 exhibited that [...] Read more.

Inositol 1,4,5-triphosphate receptor-associated cGMP kinase substrate 1 (IRAG1) is a substrate protein of the NO/cGMP-signaling pathway and forms a ternary complex with the cGMP-dependent protein kinase Iβ (PKGIβ) and the inositol triphosphate receptor I (IP₃R-I). Functional studies about IRAG1 exhibited that IRAG1 is specifically phosphorylated by the PKGIβ, regulating cGMP-mediated IP₃-dependent Ca²⁺-release. IRAG1 is widely distributed in murine tissues, e.g., in large amounts in smooth muscle-containing tissues and platelets, but also in lower amounts, e.g., in the spleen. The NO/cGMP/PKGI signaling pathway is important in several organ systems. A loss of PKGI causes gastrointestinal disorders, anemia and splenomegaly. Due to the similar tissue distribution of the PKGIβ to IRAG1, we investigated the pathophysiological functions of IRAG1 in this context. Global IRAG1-KO mice developed gastrointestinal bleeding, anemia-associated splenomegaly and iron deficiency. Additionally, Irag1-deficiency altered the protein levels of some cGMP/PKGI signaling proteins—particularly a strong decrease in the PKGIβ—in the colon, spleen and stomach but did not change mRNA-expression of the corresponding genes. The present work showed that a loss of IRAG1 and the PKGIβ/IRAG1 signaling has a crucial function in the development of gastrointestinal disorders and anemia-associated splenomegaly. Furthermore, global Irag1-deficient mice are possible in vivo model to investigate PKGIβ protein functions. Full article

(This article belongs to the Special Issue cGMP-Signaling in Cells and Tissues: Molecular, Functional, and Pharmacological Aspects)

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17 pages, 3880 KiB

Open AccessArticle

Cellular Mechanisms of the Anti-Arrhythmic Effect of Cardiac PDE2 Overexpression

by Michael Wagner, Mirna S. Sadek, Nataliya Dybkova, Fleur E. Mason, Johann Klehr, Rebecca Firneburg, Eleder Cachorro, Kurt Richter, Erik Klapproth, Stephan R. Kuenzel, Kristina Lorenz, Jordi Heijman, Dobromir Dobrev, Ali El-Armouche, Samuel Sossalla and Susanne Kämmerer

Int. J. Mol. Sci. 2021, 22(9), 4816; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22094816 - 01 May 2021

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Abstract

Background: Phosphodiesterases (PDE) critically regulate myocardial cAMP and cGMP levels. PDE2 is stimulated by cGMP to hydrolyze cAMP, mediating a negative crosstalk between both pathways. PDE2 upregulation in heart failure contributes to desensitization to β-adrenergic overstimulation. After isoprenaline (ISO) injections, PDE2 overexpressing mice [...] Read more.

Background: Phosphodiesterases (PDE) critically regulate myocardial cAMP and cGMP levels. PDE2 is stimulated by cGMP to hydrolyze cAMP, mediating a negative crosstalk between both pathways. PDE2 upregulation in heart failure contributes to desensitization to β-adrenergic overstimulation. After isoprenaline (ISO) injections, PDE2 overexpressing mice (PDE2 OE) were protected against ventricular arrhythmia. Here, we investigate the mechanisms underlying the effects of PDE2 OE on susceptibility to arrhythmias. Methods: Cellular arrhythmia, ion currents, and Ca²⁺-sparks were assessed in ventricular cardiomyocytes from PDE2 OE and WT littermates. Results: Under basal conditions, action potential (AP) morphology were similar in PDE2 OE and WT. ISO stimulation significantly increased the incidence of afterdepolarizations and spontaneous APs in WT, which was markedly reduced in PDE2 OE. The ISO-induced increase in I_CaL seen in WT was prevented in PDE2 OE. Moreover, the ISO-induced, Epac- and CaMKII-dependent increase in I_NaL and Ca²⁺-spark frequency was blunted in PDE2 OE, while the effect of direct Epac activation was similar in both groups. Finally, PDE2 inhibition facilitated arrhythmic events in ex vivo perfused WT hearts after reperfusion injury. Conclusion: Higher PDE2 abundance protects against ISO-induced cardiac arrhythmia by preventing the Epac- and CaMKII-mediated increases of cellular triggers. Thus, activating myocardial PDE2 may represent a novel intracellular anti-arrhythmic therapeutic strategy in HF. Full article

(This article belongs to the Special Issue cGMP-Signaling in Cells and Tissues: Molecular, Functional, and Pharmacological Aspects)

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18 pages, 13750 KiB

Open AccessArticle

Targeted Delivery of Soluble Guanylate Cyclase (sGC) Activator Cinaciguat to Renal Mesangial Cells via Virus-Mimetic Nanoparticles Potentiates Anti-Fibrotic Effects by cGMP-Mediated Suppression of the TGF-β Pathway

by Daniel Fleischmann, Manuela Harloff, Sara Maslanka Figueroa, Jens Schlossmann and Achim Goepferich

Int. J. Mol. Sci. 2021, 22(5), 2557; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22052557 - 04 Mar 2021

Cited by 15 | Viewed by 2906

Abstract

Diabetic nephropathy (DN) ranks among the most detrimental long-term effects of diabetes, affecting more than 30% of all patients. Within the diseased kidney, intraglomerular mesangial cells play a key role in facilitating the pro-fibrotic turnover of extracellular matrix components and a progredient glomerular [...] Read more.

Diabetic nephropathy (DN) ranks among the most detrimental long-term effects of diabetes, affecting more than 30% of all patients. Within the diseased kidney, intraglomerular mesangial cells play a key role in facilitating the pro-fibrotic turnover of extracellular matrix components and a progredient glomerular hyperproliferation. These pathological effects are in part caused by an impaired functionality of soluble guanylate cyclase (sGC) and a consequentially reduced synthesis of anti-fibrotic messenger 3′,5′-cyclic guanosine monophosphate (cGMP). Bay 58-2667 (cinaciguat) is able to re-activate defective sGC; however, the drug suffers from poor bioavailability and its systemic administration is linked to adverse events such as severe hypotension, which can hamper the therapeutic effect. In this study, cinaciguat was therefore efficiently encapsulated into virus-mimetic nanoparticles (NPs) that are able to specifically target renal mesangial cells and therefore increase the intracellular drug accumulation. NP-assisted drug delivery thereby increased in vitro potency of cinaciguat-induced sGC stabilization and activation, as well as the related downstream signaling 4- to 5-fold. Additionally, administration of drug-loaded NPs provided a considerable suppression of the non-canonical transforming growth factor β (TGF-β) signaling pathway and the resulting pro-fibrotic remodeling by 50–100%, making the system a promising tool for a more refined therapy of DN and other related kidney pathologies. Full article

(This article belongs to the Special Issue cGMP-Signaling in Cells and Tissues: Molecular, Functional, and Pharmacological Aspects)

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Review

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16 pages, 323 KiB

Open AccessReview

Pros and Cons of Pharmacological Manipulation of cGMP-PDEs in the Prevention and Treatment of Breast Cancer

by Patrizia Di Iorio, Maurizio Ronci, Patricia Giuliani, Francesco Caciagli, Renata Ciccarelli, Vanni Caruso, Sarah Beggiato and Mariachiara Zuccarini

Int. J. Mol. Sci. 2022, 23(1), 262; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23010262 - 27 Dec 2021

Cited by 12 | Viewed by 3316

Abstract

The cyclic nucleotides, cAMP and cGMP, are ubiquitous second messengers responsible for translating extracellular signals to intracellular biological responses in both normal and tumor cells. When these signals are aberrant or missing, cells may undergo neoplastic transformation or become resistant to chemotherapy. cGMP-hydrolyzing [...] Read more.

The cyclic nucleotides, cAMP and cGMP, are ubiquitous second messengers responsible for translating extracellular signals to intracellular biological responses in both normal and tumor cells. When these signals are aberrant or missing, cells may undergo neoplastic transformation or become resistant to chemotherapy. cGMP-hydrolyzing phosphodiesterases (PDEs) are attracting tremendous interest as drug targets for many diseases, including cancer, where they regulate cell growth, apoptosis and sensitization to radio- and chemotherapy. In breast cancer, PDE5 inhibition is associated with increased intracellular cGMP levels, which is responsible for the phosphorylation of PKG and other downstream molecules involved in cell proliferation or apoptosis. In this review, we provide an overview of the most relevant studies regarding the controversial role of PDE inhibitors as off-label adjuvants in cancer therapy. Full article

(This article belongs to the Special Issue cGMP-Signaling in Cells and Tissues: Molecular, Functional, and Pharmacological Aspects)

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18 pages, 4355 KiB

Open AccessReview

Structural Perspectives on the Mechanism of Soluble Guanylate Cyclase Activation

by Elizabeth C. Wittenborn and Michael A. Marletta

Int. J. Mol. Sci. 2021, 22(11), 5439; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22115439 - 21 May 2021

Cited by 18 | Viewed by 3285

Abstract

The enzyme soluble guanylate cyclase (sGC) is the prototypical nitric oxide (NO) receptor in humans and other higher eukaryotes and is responsible for transducing the initial NO signal to the secondary messenger cyclic guanosine monophosphate (cGMP). Generation of cGMP in turn leads to [...] Read more.

The enzyme soluble guanylate cyclase (sGC) is the prototypical nitric oxide (NO) receptor in humans and other higher eukaryotes and is responsible for transducing the initial NO signal to the secondary messenger cyclic guanosine monophosphate (cGMP). Generation of cGMP in turn leads to diverse physiological effects in the cardiopulmonary, vascular, and neurological systems. Given these important downstream effects, sGC has been biochemically characterized in great detail in the four decades since its discovery. Structures of full-length sGC, however, have proven elusive until very recently. In 2019, advances in single particle cryo–electron microscopy (cryo-EM) enabled visualization of full-length sGC for the first time. This review will summarize insights revealed by the structures of sGC in the unactivated and activated states and discuss their implications in the mechanism of sGC activation. Full article

(This article belongs to the Special Issue cGMP-Signaling in Cells and Tissues: Molecular, Functional, and Pharmacological Aspects)

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