International Journal of Molecular Sciences

Editorial

Jump to: Research, Review

5 pages, 185 KiB

Open AccessEditorial

Role of Phosphodiesterases in Biology and Pathology 2.0

by Mauro Giorgi, Manuela Pellegrini and Mara Massimi

Int. J. Mol. Sci. 2024, 25(10), 5339; https://doi.org/10.3390/ijms25105339 - 14 May 2024

Viewed by 1022

Abstract

Phosphodiesterases (PDEs) are ubiquitous enzymes that hydrolyse cAMP and cGMP second messengers temporally, spatially, and integratedly according to their expression and compartmentalization inside the cell [...] Full article

(This article belongs to the Special Issue Role of Phosphodiesterase in Biology and Pathology 2.0)

Research

Jump to: Editorial, Review

14 pages, 2092 KiB

Open AccessArticle

Close Relationship between Systemic Arterial and Portal Venous Pressure in an Animal Model with Healthy Liver

by Adhara Lazaro, Patrick Stoll, Dominik von Elverfeldt, Wolfgang Kreisel and Peter Deibert

Int. J. Mol. Sci. 2023, 24(12), 9963; https://doi.org/10.3390/ijms24129963 - 9 Jun 2023

Viewed by 1655

Abstract

It is unclear to what extent systemic arterial blood pressure influences portal pressure. This relationship is clinically important as drugs, which are conventionally used for therapy of portal hypertension, may also influence systemic arterial blood pressure. This study investigated the potential correlation between [...] Read more.

It is unclear to what extent systemic arterial blood pressure influences portal pressure. This relationship is clinically important as drugs, which are conventionally used for therapy of portal hypertension, may also influence systemic arterial blood pressure. This study investigated the potential correlation between mean arterial (MAP) and portal venous pressure (PVP) in rats with healthy livers. In a rat model with healthy livers, we investigated the effect of manipulation of MAP on PVP. Interventions consisted of 0.9% NaCl (group 1), 0.1 mg/kg body weight (bw) Sildenafil (low dose), an inhibitor of phosphodiesterase-5 (group 2), and 1.0 mg/kg bw Sildenafil (high dose, group 3) in 600 µL saline injected intravenously. Norepinephrine was used to increase MAP in animals with circulatory failure while PVP was monitored. Injection of the fluids induced a transient drop in MAP and PVP, probably due to a reversible cardiac decompensation. The drop in MAP and drop in PVP are significantly correlated. The time lag between change in MAP and change in PVP by 24 s in all groups suggests a cause-and-effect relationship. Ten minutes after the injection of the fluid, cardiac function was normalized. Thereafter, MAP gradually decreased. In the NaCl group, PVP decreases by 0.485% for a 1% drop of MAP, by 0.550% in the low-dose sildenafil group, and by 0.651% in the high-dose sildenafil group (p < 0.05 for difference group two vs. group one, group three vs. group one, and group three vs. group two). These data suggest that Sildenafil has an inherent effect on portal pressure that exceeds the effect of MAP. Injection of norepinephrine led to a sudden increase in MAP followed by an increase in PVP after a time lag. These data show a close relationship between portal venous pressure and systemic arterial pressure in this animal model with healthy livers. A change in MAP is consequently followed by a change in PVP after a distinct time lag. This study, furthermore, suggests that Sildenafil influences portal pressure. Further studies should be performed in a model with cirrhotic livers, as these may be important in the evaluation of vasoactive drugs (e.g., PDE-5-inhibitors) for therapy of portal hypertension. Full article

(This article belongs to the Special Issue Role of Phosphodiesterase in Biology and Pathology 2.0)

► Show Figures

Figure 1

18 pages, 10620 KiB

Open AccessArticle

To Target or Not to Target Schistosoma mansoni Cyclic Nucleotide Phosphodiesterase 4A?

by Yang Zheng, Susanne Schroeder, Georgi K. Kanev, Sanaa S. Botros, Samia William, Abdel-Nasser A. Sabra, Louis Maes, Guy Caljon, Carmen Gil, Ana Martinez, Irene G. Salado, Koen Augustyns, Ewald Edink, Maarten Sijm, Erik de Heuvel, Iwan J. P. de Esch, Tiffany van der Meer, Marco Siderius, Geert Jan Sterk, David Brown and Rob Leurs Show full author list Hide full author list

Int. J. Mol. Sci. 2023, 24(7), 6817; https://doi.org/10.3390/ijms24076817 - 6 Apr 2023

Cited by 1 | Viewed by 1973

Abstract

Schistosomiasis is a neglected tropical disease with high morbidity. Recently, the Schistosoma mansoni phosphodiesterase SmPDE4A was suggested as a putative new drug target. To support SmPDE4A targeted drug discovery, we cloned, isolated, and biochemically characterized the full-length and catalytic domains of SmPDE4A. The [...] Read more.

Schistosomiasis is a neglected tropical disease with high morbidity. Recently, the Schistosoma mansoni phosphodiesterase SmPDE4A was suggested as a putative new drug target. To support SmPDE4A targeted drug discovery, we cloned, isolated, and biochemically characterized the full-length and catalytic domains of SmPDE4A. The enzymatically active catalytic domain was crystallized in the apo-form (PDB code: 6FG5) and in the cAMP- and AMP-bound states (PDB code: 6EZU). The SmPDE4A catalytic domain resembles human PDE4 more than parasite PDEs because it lacks the parasite PDE-specific P-pocket. Purified SmPDE4A proteins (full-length and catalytic domain) were used to profile an in-house library of PDE inhibitors (PDE4NPD toolbox). This screening identified tetrahydrophthalazinones and benzamides as potential hits. The PDE inhibitor NPD-0001 was the most active tetrahydrophthalazinone, whereas the approved human PDE4 inhibitors roflumilast and piclamilast were the most potent benzamides. As a follow-up, 83 benzamide analogs were prepared, but the inhibitory potency of the initial hits was not improved. Finally, NPD-0001 and roflumilast were evaluated in an in vitro anti-S. mansoni assay. Unfortunately, both SmPDE4A inhibitors were not effective in worm killing and only weakly affected the egg-laying at high micromolar concentrations. Consequently, the results with these SmPDE4A inhibitors strongly suggest that SmPDE4A is not a suitable target for anti-schistosomiasis therapy. Full article

(This article belongs to the Special Issue Role of Phosphodiesterase in Biology and Pathology 2.0)

► Show Figures

Figure 1

14 pages, 1279 KiB

Open AccessArticle

Phosphodiesterase 5a Signalling in Skeletal Muscle Pathophysiology

by Valeria De Arcangelis, Luciana De Angelis, Federica Barbagallo, Federica Campolo, Ana Gabriela de Oliveira do Rego, Manuela Pellegrini, Fabio Naro, Mauro Giorgi and Lucia Monaco

Int. J. Mol. Sci. 2023, 24(1), 703; https://doi.org/10.3390/ijms24010703 - 31 Dec 2022

Cited by 2 | Viewed by 2419

Abstract

Phosphodiesterase 5A (PDE5A) is involved in cGMP hydrolysis, regulating many physiological processes. Increased activity of PDE5A has been found in several pathological conditions, and the pharmacological inhibition of PDE5 has been demonstrated to have several therapeutic applications. We have identified the presence of [...] Read more.

Phosphodiesterase 5A (PDE5A) is involved in cGMP hydrolysis, regulating many physiological processes. Increased activity of PDE5A has been found in several pathological conditions, and the pharmacological inhibition of PDE5 has been demonstrated to have several therapeutic applications. We have identified the presence of three different Pde5a isoforms in cardiomyocytes, and we have found that the expression of specific Pde5a isoforms may have a causal role in the onset of pathological responses in these cells. In our previous study, we demonstrated that PDE5A inhibition could ameliorate muscular dystrophy by acting at different levels, as assessed by the altered genomic response of muscular cells following treatment with the PDE5A inhibitor tadalafil. Thus, considering the importance of PDE5A in various pathophysiological conditions, we further investigated the regulation of this enzyme. Here, we analysed the expression of Pde5a isoforms in the pathophysiology of skeletal muscle. We found that skeletal muscle tissues and myogenic cells express Pde5a1 and Pde5a2 isoforms, and we observed an increased expression of Pde5a1 in damaged skeletal muscles, while Pde5a2 levels remained unchanged. We also cloned and characterized the promoters that control the transcription of Pde5a isoforms, investigating which of the transcription factors predicted by bioinformatics analysis could be involved in their modulation. In conclusion, we found an overexpression of Pde5a1 in compromised muscle and identified an involvement of MyoD and Runx1 in Pde5a1 transcriptional activity. Full article

(This article belongs to the Special Issue Role of Phosphodiesterase in Biology and Pathology 2.0)

► Show Figures

Figure 1

12 pages, 4631 KiB

Open AccessArticle

The Dual PDE7-GSK3β Inhibitor, VP3.15, as Neuroprotective Disease-Modifying Treatment in a Model of Primary Progressive Multiple Sclerosis

by Rocio Benítez-Fernández, Carmen Gil, Carmen Guaza, Leyre Mestre and Ana Martínez

Int. J. Mol. Sci. 2022, 23(22), 14378; https://doi.org/10.3390/ijms232214378 - 19 Nov 2022

Cited by 10 | Viewed by 1733

Abstract

Multiple sclerosis (MS) is a chronic, inflammatory, autoimmune and degenerative disease with axonal damage and demyelination as its main features. Its dual neurological and autoimmune nature makes it a disease that is difficult to treat. Treatments that simultaneously stop the immune response while [...] Read more.

Multiple sclerosis (MS) is a chronic, inflammatory, autoimmune and degenerative disease with axonal damage and demyelination as its main features. Its dual neurological and autoimmune nature makes it a disease that is difficult to treat. Treatments that simultaneously stop the immune response while protecting and repairing the nervous system are urgent. That is of utmost importance for the primary progressive multiple sclerosis (PPMS), a rare and severe variant of MS, characterized by worsening neurological function from the onset of symptoms. In this sense, inhibitors of glycogen synthase kinase 3β (GSK3β) and phosphodiesterase 7 (PDE7) have recently shown great therapeutic potential for the treatment of demyelinating diseases. Here we investigated a dual inhibitor of these two targets, the small molecule VP3.15, in a preclinical model, which resembles primary-progressive MS (PPMS), the Theiler’s mouse encephalomyelitis virus-induced demyelinated disease (TMEV-IDD). In our study, VP3.15 ameliorates the disease course improving motor deficits of infected mice. Chronic treatment with VP3.15 also showed significant efficacy in the immunomodulation process, as well as in the proliferation and differentiation of oligodendroglial precursors, improving the preservation of myelin and axonal integrity. Therefore, our results support a treatment with the safe VP3.15 as an integrative therapeutic strategy for the treatment of PPMS. Full article

(This article belongs to the Special Issue Role of Phosphodiesterase in Biology and Pathology 2.0)

► Show Figures

Figure 1

18 pages, 2374 KiB

Open AccessArticle

Cellular Redox Metabolism Is Modulated by the Distinct Localization of Cyclic Nucleotide Phosphodiesterase 5A Isoforms

by Silvia Cardarelli, Adriana Erica Miele, Federica Campolo, Mara Massimi, Patrizia Mancini, Stefano Biagioni, Fabio Naro, Mauro Giorgi and Michele Saliola

Int. J. Mol. Sci. 2022, 23(15), 8587; https://doi.org/10.3390/ijms23158587 - 2 Aug 2022

Cited by 4 | Viewed by 1900

Abstract

3′-5′ cyclic nucleotide phosphodiesterases (PDEs) are a family of evolutionarily conserved cAMP and/or cGMP hydrolyzing enzymes, components of transduction pathways regulating crucial aspects of cell life. Among them, cGMP-specific PDE5—being a regulator of vascular smooth muscle contraction—is the molecular target of several drugs [...] Read more.

3′-5′ cyclic nucleotide phosphodiesterases (PDEs) are a family of evolutionarily conserved cAMP and/or cGMP hydrolyzing enzymes, components of transduction pathways regulating crucial aspects of cell life. Among them, cGMP-specific PDE5—being a regulator of vascular smooth muscle contraction—is the molecular target of several drugs used to treat erectile dysfunction and pulmonary hypertension. Production of full-length murine PDE5A isoforms in the milk-yeast Kluyveromyces lactis showed that the quaternary assembly of MmPDE5A1 is a mixture of dimers and tetramers, while MmPDE5A2 and MmPDE5A3 only assembled as dimers. We showed that the N-terminal peptide is responsible for the tetramer assembly of MmPDE5A1, while that of the MmPDE5A2 is responsible for its mitochondrial localization. Overexpression of the three isoforms alters at different levels the cAMP/cGMP equilibrium as well as the NAD(P)⁺/NAD(P)H balance and induces a metabolic switch from oxidative to fermentative. In particular, the mitochondrial localization of MmPDE5A2 unveiled the existence of a cAMP-cGMP signaling cascade in this organelle, for which we propose a metabolic model that could explain the role of PDE5 in some cardiomyopathies and some of the side effects of its inhibitors. Full article

(This article belongs to the Special Issue Role of Phosphodiesterase in Biology and Pathology 2.0)

► Show Figures

Figure 1

11 pages, 10711 KiB

Open AccessArticle

Crosstalk between β2- and α2-Adrenergic Receptors in the Regulation of B16F10 Melanoma Cell Proliferation

by Paola Matarrese, Sonia Maccari, Barbara Ascione, Rosa Vona, Vanessa Vezzi, Tonino Stati, Maria Cristina Grò, Giuseppe Marano, Caterina Ambrosio and Paola Molinari

Int. J. Mol. Sci. 2022, 23(9), 4634; https://doi.org/10.3390/ijms23094634 - 22 Apr 2022

Cited by 3 | Viewed by 2622

Abstract

Adrenergic receptors (AR) belong to the G protein-coupled receptor superfamily and regulate migration and proliferation in various cell types. The objective of this study was to evaluate whether β-AR stimulation affects the antiproliferative action of α2-AR agonists on B16F10 cells and, if so, [...] Read more.

Adrenergic receptors (AR) belong to the G protein-coupled receptor superfamily and regulate migration and proliferation in various cell types. The objective of this study was to evaluate whether β-AR stimulation affects the antiproliferative action of α2-AR agonists on B16F10 cells and, if so, to determine the relative contribution of β-AR subtypes. Using pharmacological approaches, evaluation of Ki-67 expression by flow cytometry and luciferase-based cAMP assay, we found that treatment with isoproterenol, a β-AR agonist, increased cAMP levels in B16F10 melanoma cells without affecting cell proliferation. Propranolol inhibited the cAMP response to isoproterenol. In addition, stimulation of α2-ARs with agonists such as clonidine, a well-known antihypertensive drug, decreased cancer cell proliferation. This effect on cell proliferation was suppressed by treatment with isoproterenol. In turn, the suppressive effects of isoproterenol were abolished by the treatment with either ICI 118,551, a β2-AR antagonist, or propranolol, suggesting that isoproterenol effects are mainly mediated by the β2-AR stimulation. We conclude that the crosstalk between the β2-AR and α2-AR signaling pathways regulates the proliferative activity of B16F10 cells and may therefore represent a therapeutic target for melanoma therapy. Full article

(This article belongs to the Special Issue Role of Phosphodiesterase in Biology and Pathology 2.0)

► Show Figures

Graphical abstract

12 pages, 1450 KiB

Open AccessArticle

Phosphodiesterases Expression during Murine Cardiac Development

by Thays Maria da Conceição Silva Carvalho, Silvia Cardarelli, Mauro Giorgi, Andrea Lenzi, Andrea M. Isidori and Fabio Naro

Int. J. Mol. Sci. 2021, 22(5), 2593; https://doi.org/10.3390/ijms22052593 - 5 Mar 2021

Cited by 3 | Viewed by 2341

Abstract

3′-5′ cyclic nucleotide phosphodiesterases (PDEs) are a large family of enzymes playing a fundamental role in the control of intracellular levels of cAMP and cGMP. Emerging evidence suggested an important role of phosphodiesterases in heart formation, but little is known about the expression [...] Read more.

3′-5′ cyclic nucleotide phosphodiesterases (PDEs) are a large family of enzymes playing a fundamental role in the control of intracellular levels of cAMP and cGMP. Emerging evidence suggested an important role of phosphodiesterases in heart formation, but little is known about the expression of phosphodiesterases during cardiac development. In the present study, the pattern of expression and enzymatic activity of phosphodiesterases was investigated at different stages of heart formation. C57BL/6 mice were mated and embryos were collected from 14.5 to 18.5 days of development. Data obtained by qRT-PCR and Western blot analysis showed that seven different isoforms are expressed during heart development, and PDE1C, PDE2A, PDE4D, PDE5A and PDE8A are modulated from E14.5 to E18.5. In heart homogenates, the total cAMP and cGMP hydrolytic activity is constant at the evaluated times, and PDE4 accounts for the majority of the cAMP hydrolyzing ability and PDE2A accounts for cGMP hydrolysis. This study showed that a subset of PDEs is expressed in developing mice heart and some of them are modulated to maintain constant nucleotide phosphodiesterase activity in embryonic and fetal heart. Full article

(This article belongs to the Special Issue Role of Phosphodiesterase in Biology and Pathology)

► Show Figures

Figure 1

13 pages, 1860 KiB

Open AccessArticle

Influence of Phosphodiesterase Inhibition on CRE- and EGR1-Dependent Transcription in a Mouse Hippocampal Cell Line

by Erik Maronde

Int. J. Mol. Sci. 2020, 21(22), 8658; https://doi.org/10.3390/ijms21228658 - 17 Nov 2020

Cited by 4 | Viewed by 2275

Abstract

Signaling pathways, depending on the second messenger molecule cAMP, modulate hippocampal cell signaling via influencing transcription factors like cAMP-regulated element-binding protein (CREB) or early growth response 1 EGR1/Krox24/zif268/ZENK (EGR1). Here, we investigated two reporter cell lines derived from an immortalized hippocampal neuronal cell [...] Read more.

Signaling pathways, depending on the second messenger molecule cAMP, modulate hippocampal cell signaling via influencing transcription factors like cAMP-regulated element-binding protein (CREB) or early growth response 1 EGR1/Krox24/zif268/ZENK (EGR1). Here, we investigated two reporter cell lines derived from an immortalized hippocampal neuronal cell line stably expressing a CRE- or EGR1-luciferase reporter gene (HT22CREluc and HT22EGR1luc, respectively). The cells were subjected to phosphodiesterase inhibitors and other cAMP-modulating agents to investigate dose- and time-dependent phosphodiesterase (PDE)-mediated fine-tuning of cAMP-dependent transcriptional signaling. The non-isoform-specific cyclic nucleotide phosphodiesterase (PDE) inhibitor isobutyl-methyl-xanthine (IBMX), as well as selective inhibitors of PDE3 (milrinone) and PDE4 (rolipram), were tested for their ability to elevate CRE- and EGR1-luciferase activity. Pharmacological parameters like onset of activity, maximum activity, and offset of activity were determined. In summary, phosphodiesterase inhibition appeared similarly potent in comparison to adenylate cyclase stimulation or direct activation of protein kinase A (PKA) via specific cAMP agonists and was at least partly mediated by PKA as shown by the selective PKA inhibitor Rp-8-Br-cAMPS. Moreover, transcriptional activation by PDE inhibition was also influenced by organic anion-exchanger action and interacted with fibroblast growth factor (FGF) receptor-mediated pathways. Full article

(This article belongs to the Special Issue Role of Phosphodiesterase in Biology and Pathology)

► Show Figures

Graphical abstract

19 pages, 3519 KiB

Open AccessArticle

Multi-Compartment, Early Disruption of cGMP and cAMP Signalling in Cardiac Myocytes from the mdx Model of Duchenne Muscular Dystrophy

by Marcella Brescia, Ying-Chi Chao, Andreas Koschinski, Jakub Tomek and Manuela Zaccolo

Int. J. Mol. Sci. 2020, 21(19), 7056; https://doi.org/10.3390/ijms21197056 - 25 Sep 2020

Cited by 10 | Viewed by 3416

Abstract

Duchenne muscular dystrophy (DMD) is the most frequent and severe form of muscular dystrophy. The disease presents with progressive body-wide muscle deterioration and, with recent advances in respiratory care, cardiac involvement is an important cause of morbidity and mortality. DMD is caused by [...] Read more.

Duchenne muscular dystrophy (DMD) is the most frequent and severe form of muscular dystrophy. The disease presents with progressive body-wide muscle deterioration and, with recent advances in respiratory care, cardiac involvement is an important cause of morbidity and mortality. DMD is caused by mutations in the dystrophin gene resulting in the absence of dystrophin and, consequently, disturbance of other proteins that form the dystrophin-associated protein complex (DAPC), including neuronal nitric oxide synthase (nNOS). The molecular mechanisms that link the absence of dystrophin with the alteration of cardiac function remain poorly understood but disruption of NO-cGMP signalling, mishandling of calcium and mitochondrial disturbances have been hypothesized to play a role. cGMP and cAMP are second messengers that are key in the regulation of cardiac myocyte function and disruption of cyclic nucleotide signalling leads to cardiomyopathy. cGMP and cAMP signals are compartmentalised and local regulation relies on the activity of phosphodiesterases (PDEs). Here, using genetically encoded FRET reporters targeted to distinct subcellular compartments of neonatal cardiac myocytes from the DMD mouse model mdx, we investigate whether lack of dystrophin disrupts local cyclic nucleotide signalling, thus potentially providing an early trigger for the development of cardiomyopathy. Our data show a significant alteration of both basal and stimulated cyclic nucleotide levels in all compartments investigated, as well as a complex reorganization of local PDE activities. Full article

(This article belongs to the Special Issue Role of Phosphodiesterase in Biology and Pathology)

► Show Figures

Figure 1

18 pages, 1346 KiB

Open AccessArticle

In Vitro Inhibition of Phosphodiesterase 3B (PDE 3B) by Anthocyanin-Rich Fruit Juice Extracts and Selected Anthocyanins

by Celina Göttel, Sonja Niesen, Vanessa Daub, Theresa Werle, Tamara Bakuradze, Peter Winterhalter and Elke Richling

Int. J. Mol. Sci. 2020, 21(18), 6934; https://doi.org/10.3390/ijms21186934 - 21 Sep 2020

Cited by 11 | Viewed by 2731

Abstract

Phosphodiesterases (PDEs) are essential enzymes for the regulation of pathways mediated by cyclic adenosine monophosphate (cAMP). Secondary plant compounds like anthocyanins (ACs) can inhibit PDE activity and, consequently, may be beneficial for lipid metabolism. This study investigated 18 AC-rich juice extracts and pure [...] Read more.

Phosphodiesterases (PDEs) are essential enzymes for the regulation of pathways mediated by cyclic adenosine monophosphate (cAMP). Secondary plant compounds like anthocyanins (ACs) can inhibit PDE activity and, consequently, may be beneficial for lipid metabolism. This study investigated 18 AC-rich juice extracts and pure reference compounds from red fruits for potential inhibitory effects on PDE 3B activity. Extracts were obtained through adsorption on Amberlite^® XAD 7 resin. Based on this screening, the chokeberry, blueberry, pomegranate, and cranberry extracts were active, with half maximal inhibitory concentrations (IC₅₀) ranging from 163 ± 3 µg/mL to 180 ± 3 µg/mL. The ACs in these extracts, peonidin-3-glucoside and cyanidin-3-arabinoside, were the most active single compounds (IC₅₀ = 56 ± 20 µg/mL, 108 ± 6 µg/mL). All extracts comprised high amounts of phenolic compounds, as determined by the Folin–Ciocalteu assay, ranging from 39.8 ± 1.5 to 73.5 ± 4.8 g gallic acid equivalents (GAE)/100 g extract. Pomegranate and chokeberry extracts exhibited the largest amounts of polyphenols (72.3 ± 0.7 g GAE/100 g, 70.6 ± 4.1 g GAE/100 g, respectively). Overall, our results showed that fruit juice extracts and their ACs can inhibit PDE activity. Any potential health benefits in vivo will be investigated in the future. Full article

(This article belongs to the Special Issue Role of Phosphodiesterase in Biology and Pathology)

► Show Figures

Figure 1

25 pages, 1878 KiB

Open AccessArticle

Dominant-Negative Attenuation of cAMP-Selective Phosphodiesterase PDE4D Action Affects Learning and Behavior

by Graeme B. Bolger, Lisa High Mitchell Smoot and Thomas van Groen

Int. J. Mol. Sci. 2020, 21(16), 5704; https://doi.org/10.3390/ijms21165704 - 9 Aug 2020

Cited by 7 | Viewed by 4028

Abstract

PDE4 cyclic nucleotide phosphodiesterases reduce 3′, 5′ cAMP levels in the CNS and thereby regulate PKA activity and the phosphorylation of CREB, fundamental to depression, cognition, and learning and memory. The PDE4 isoform PDE4D5 interacts with the signaling proteins β-arrestin2 and RACK1, regulators [...] Read more.

PDE4 cyclic nucleotide phosphodiesterases reduce 3′, 5′ cAMP levels in the CNS and thereby regulate PKA activity and the phosphorylation of CREB, fundamental to depression, cognition, and learning and memory. The PDE4 isoform PDE4D5 interacts with the signaling proteins β-arrestin2 and RACK1, regulators of β₂-adrenergic and other signal transduction pathways. Mutations in PDE4D in humans predispose to acrodysostosis, associated with cognitive and behavioral deficits. To target PDE4D5, we developed mice that express a PDE4D5-D556A dominant-negative transgene in the brain. Male transgenic mice demonstrated significant deficits in hippocampus-dependent spatial learning, as assayed in the Morris water maze. In contrast, associative learning, as assayed in a fear conditioning assay, appeared to be unaffected. Male transgenic mice showed augmented activity in prolonged (2 h) open field testing, while female transgenic mice showed reduced activity in the same assay. Transgenic mice showed no demonstrable abnormalities in prepulse inhibition. There was also no detectable difference in anxiety-like behavior, as measured in the elevated plus-maze. These data support the use of a dominant-negative approach to the study of PDE4D5 function in the CNS and specifically in learning and memory. Full article

(This article belongs to the Special Issue Role of Phosphodiesterase in Biology and Pathology)

► Show Figures

Figure 1

11 pages, 1964 KiB

Open AccessArticle

Chronic Sildenafil Treatment Improves Vasomotor Function in a Mouse Model of Accelerated Aging

by Keivan Golshiri, Ehsan Ataei Ataabadi, Renata Brandt, Ingrid van der Pluijm, René de Vries, A. H. Jan Danser and Anton Roks

Int. J. Mol. Sci. 2020, 21(13), 4667; https://doi.org/10.3390/ijms21134667 - 30 Jun 2020

Cited by 12 | Viewed by 3682

Abstract

Aging leads to a loss of vasomotor control. Both vasodilation and vasoconstriction are affected. Decreased nitric oxide–cGMP-mediated relaxation is a hallmark of aging. It contributes to vascular disease, notably hypertension, infarction, and dementia. Decreased vasodilation can be caused by aging independently from cardiovascular [...] Read more.

Aging leads to a loss of vasomotor control. Both vasodilation and vasoconstriction are affected. Decreased nitric oxide–cGMP-mediated relaxation is a hallmark of aging. It contributes to vascular disease, notably hypertension, infarction, and dementia. Decreased vasodilation can be caused by aging independently from cardiovascular risk factors. This process that can be mimicked in mice in an accelerated way by activation of the DNA damage response. Genetic deletion of the DNA repair enzyme ERCC1 endonuclease in mice, as in the case of Ercc1^Δ/- mice, can be used as a tool to accelerate aging. Ercc1^Δ/- mice develop age-dependent vasomotor dysfunction from two months after birth. In the present study we tested if chronic treatment with sildenafil, a phosphodiesterase 5 inhibitor that augments NO–cGMP signaling, can reduce the development of vasomotor dysfunction in Ercc1^Δ/- mice. Ercc1^Δ/- mice and wild-type littermates were treated with 10 mg/kg/d of sildenafil from the age of 6 to the age of 14 weeks. Blood pressure and in vivo and ex vivo vasomotor responses were measured at the end of the treatment period. Ercc1^Δ/- mice developed decreased reactive hyperemia, and diminished NO–cGMP-dependent acetylcholine responses. The diminished acetylcholine response involved both endothelial and vascular smooth muscle cell signaling. Chronic sildenafil exclusively improved NO–cGMP signaling in VSMC, and had no effect on endothelium-derived hyperpolarization. Sildenafil also improved KCl hypocontractility in Ercc1^Δ/- mice. All effects were blood pressure-independent. The findings might be of clinical importance for prevention of morbidities related to vascular aging as well as for progeria patients with a high risk of cardiovascular disease. Full article

(This article belongs to the Special Issue Role of Phosphodiesterase in Biology and Pathology)

► Show Figures

Figure 1

17 pages, 3450 KiB

Open AccessArticle

PDE2A Is Indispensable for Mouse Liver Development and Hematopoiesis

by Federica Barbagallo, Valentina Rotilio, Maria Rita Assenza, Salvatore Aguanno, Tiziana Orsini, Sabrina Putti, Andrea M. Isidori, Andrea Lenzi, Fabio Naro, Luciana De Angelis and Manuela Pellegrini

Int. J. Mol. Sci. 2020, 21(8), 2902; https://doi.org/10.3390/ijms21082902 - 21 Apr 2020

Cited by 9 | Viewed by 3633

Abstract

Phosphodiesterase 2A (PDE2A) is a cAMP-cGMP hydrolyzing enzyme essential for mouse development and the PDE2A knockout model (PDE2A^−/−) is embryonic lethal. Notably, livers of PDE2A^−/− embryos at embryonic day 14.5 (E14.5) have extremely reduced size. Morphological, cellular and molecular [...] Read more.

Phosphodiesterase 2A (PDE2A) is a cAMP-cGMP hydrolyzing enzyme essential for mouse development and the PDE2A knockout model (PDE2A^−/−) is embryonic lethal. Notably, livers of PDE2A^−/− embryos at embryonic day 14.5 (E14.5) have extremely reduced size. Morphological, cellular and molecular analyses revealed loss of integrity in the PDE2A^−/− liver niche that compromises the hematopoietic function and maturation. Hematopoietic cells isolated from PDE2A^−/− livers are instead able to differentiate in in vitro assays, suggesting the absence of blood cell-autonomous defects. Apoptosis was revealed in hepatoblasts and at the endothelial and stromal compartments in livers of PDE2A^−/− embryos. The increase of the intracellular cAMP level and of the inducible cAMP early repressor (ICER) in liver of PDE2A^−/− embryos might explain the impairment of liver development by downregulating the expression of the anti-apoptotic gene Bcl2. In summary, we propose PDE2A as an essential gene for integrity maintenance of liver niche and the accomplishment of hematopoiesis. Full article

(This article belongs to the Special Issue Role of Phosphodiesterase in Biology and Pathology)

► Show Figures

Figure 1

Review

Jump to: Editorial, Research

21 pages, 837 KiB

Open AccessReview

Unleashing Spinal Cord Repair: The Role of cAMP-Specific PDE Inhibition in Attenuating Neuroinflammation and Boosting Regeneration after Traumatic Spinal Cord Injury

by Femke Mussen, Jana Van Broeckhoven, Niels Hellings, Melissa Schepers and Tim Vanmierlo

Int. J. Mol. Sci. 2023, 24(9), 8135; https://doi.org/10.3390/ijms24098135 - 2 May 2023

Cited by 5 | Viewed by 2554

Abstract

Traumatic spinal cord injury (SCI) is characterized by severe neuroinflammation and hampered neuroregeneration, which often leads to permanent neurological deficits. Current therapies include decompression surgery, rehabilitation, and in some instances, the use of corticosteroids. However, the golden standard of corticosteroids still achieves minimal [...] Read more.

Traumatic spinal cord injury (SCI) is characterized by severe neuroinflammation and hampered neuroregeneration, which often leads to permanent neurological deficits. Current therapies include decompression surgery, rehabilitation, and in some instances, the use of corticosteroids. However, the golden standard of corticosteroids still achieves minimal improvements in functional outcomes. Therefore, new strategies tackling the initial inflammatory reactions and stimulating endogenous repair in later stages are crucial to achieving functional repair in SCI patients. Cyclic adenosine monophosphate (cAMP) is an important second messenger in the central nervous system (CNS) that modulates these processes. A sustained drop in cAMP levels is observed during SCI, and elevating cAMP is associated with improved functional outcomes in experimental models. cAMP is regulated in a spatiotemporal manner by its hydrolyzing enzyme phosphodiesterase (PDE). Growing evidence suggests that inhibition of cAMP-specific PDEs (PDE4, PDE7, and PDE8) is an important strategy to orchestrate neuroinflammation and regeneration in the CNS. Therefore, this review focuses on the current evidence related to the immunomodulatory and neuroregenerative role of cAMP-specific PDE inhibition in the SCI pathophysiology. Full article

(This article belongs to the Special Issue Role of Phosphodiesterase in Biology and Pathology 2.0)

► Show Figures

Figure 1

24 pages, 4283 KiB

Open AccessReview

Phosphodiesterases and Compartmentation of cAMP and cGMP Signaling in Regulation of Cardiac Contractility in Normal and Failing Hearts

by Gaia Calamera, Lise Román Moltzau, Finn Olav Levy and Kjetil Wessel Andressen

Int. J. Mol. Sci. 2022, 23(4), 2145; https://doi.org/10.3390/ijms23042145 - 15 Feb 2022

Cited by 24 | Viewed by 6180

Abstract

Cardiac contractility is regulated by several neural, hormonal, paracrine, and autocrine factors. Amongst these, signaling through β-adrenergic and serotonin receptors generates the second messenger cyclic AMP (cAMP), whereas activation of natriuretic peptide receptors and soluble guanylyl cyclases generates cyclic GMP (cGMP). Both cyclic [...] Read more.

Cardiac contractility is regulated by several neural, hormonal, paracrine, and autocrine factors. Amongst these, signaling through β-adrenergic and serotonin receptors generates the second messenger cyclic AMP (cAMP), whereas activation of natriuretic peptide receptors and soluble guanylyl cyclases generates cyclic GMP (cGMP). Both cyclic nucleotides regulate cardiac contractility through several mechanisms. Phosphodiesterases (PDEs) are enzymes that degrade cAMP and cGMP and therefore determine the dynamics of their downstream effects. In addition, the intracellular localization of the different PDEs may contribute to regulation of compartmented signaling of cAMP and cGMP. In this review, we will focus on the role of PDEs in regulating contractility and evaluate changes in heart failure. Full article

(This article belongs to the Special Issue Role of Phosphodiesterase in Biology and Pathology 2.0)

► Show Figures

Figure 1

19 pages, 1363 KiB

Open AccessReview

Clinical Implication of Phosphodiesterase-4-Inhibition

by Martin Alexander Schick and Nicolas Schlegel

Int. J. Mol. Sci. 2022, 23(3), 1209; https://doi.org/10.3390/ijms23031209 - 21 Jan 2022

Cited by 37 | Viewed by 4299

Abstract

The pleiotropic function of 3′,5′-cyclic adenosine monophosphate (cAMP)-dependent pathways in health and disease led to the development of pharmacological phosphodiesterase inhibitors (PDE-I) to attenuate cAMP degradation. While there are many isotypes of PDE, a predominant role of PDE4 is to regulate fundamental functions, [...] Read more.

The pleiotropic function of 3′,5′-cyclic adenosine monophosphate (cAMP)-dependent pathways in health and disease led to the development of pharmacological phosphodiesterase inhibitors (PDE-I) to attenuate cAMP degradation. While there are many isotypes of PDE, a predominant role of PDE4 is to regulate fundamental functions, including endothelial and epithelial barrier stability, modulation of inflammatory responses and cognitive and/or mood functions. This makes the use of PDE4-I an interesting tool for various therapeutic approaches. However, due to the presence of PDE4 in many tissues, there is a significant danger for serious side effects. Based on this, the aim of this review is to provide a comprehensive overview of the approaches and effects of PDE4-I for different therapeutic applications. In summary, despite many obstacles to use of PDE4-I for different therapeutic approaches, the current data warrant future research to utilize the therapeutic potential of phosphodiesterase 4 inhibition. Full article

(This article belongs to the Special Issue Role of Phosphodiesterase in Biology and Pathology 2.0)

► Show Figures

Figure 1

18 pages, 3830 KiB

Open AccessReview

Cyclic GMP in Liver Cirrhosis—Role in Pathophysiology of Portal Hypertension and Therapeutic Implications

by Wolfgang Kreisel, Adhara Lazaro, Jonel Trebicka, Markus Grosse Perdekamp, Annette Schmitt-Graeff and Peter Deibert

Int. J. Mol. Sci. 2021, 22(19), 10372; https://doi.org/10.3390/ijms221910372 - 26 Sep 2021

Cited by 12 | Viewed by 5170

Abstract

The NO-cGMP signal transduction pathway plays a crucial role in tone regulation in hepatic sinusoids and peripheral blood vessels. In a cirrhotic liver, the key enzymes endothelial NO synthase (eNOS), soluble guanylate cyclase (sGC), and phosphodiesterase-5 (PDE-5) are overexpressed, leading to decreased cyclic [...] Read more.

The NO-cGMP signal transduction pathway plays a crucial role in tone regulation in hepatic sinusoids and peripheral blood vessels. In a cirrhotic liver, the key enzymes endothelial NO synthase (eNOS), soluble guanylate cyclase (sGC), and phosphodiesterase-5 (PDE-5) are overexpressed, leading to decreased cyclic guanosine-monophosphate (cGMP). This results in constriction of hepatic sinusoids, contributing about 30% of portal pressure. In contrast, in peripheral arteries, dilation prevails with excess cGMP due to low PDE-5. Both effects eventually lead to circulatory dysfunction in progressed liver cirrhosis. The conventional view of portal hypertension (PH) pathophysiology has been described using the “NO-paradox”, referring to reduced NO availability inside the liver and elevated NO production in the peripheral systemic circulation. However, recent data suggest that an altered availability of cGMP could better elucidate the contrasting findings of intrahepatic vasoconstriction and peripheral systemic vasodilation than mere focus on NO availability. Preclinical and clinical data have demonstrated that targeting the NO-cGMP pathway in liver cirrhosis using PDE-5 inhibitors or sGC stimulators/activators decreases intrahepatic resistance through dilation of sinusoids, lowering portal pressure, and increasing portal venous blood flow. These results suggest further clinical applications in liver cirrhosis. Targeting the NO-cGMP system plays a role in possible reversal of liver fibrosis or cirrhosis. PDE-5 inhibitors may have therapeutic potential for hepatic encephalopathy. Serum/plasma levels of cGMP can be used as a non-invasive marker of clinically significant portal hypertension. This manuscript reviews new data about the role of the NO-cGMP signal transduction system in pathophysiology of cirrhotic portal hypertension and provides perspective for further studies. Full article

(This article belongs to the Special Issue Role of Phosphodiesterase in Biology and Pathology 2.0)

► Show Figures

Figure 1

44 pages, 8881 KiB

Open AccessReview

Challenges on Cyclic Nucleotide Phosphodiesterases Imaging with Positron Emission Tomography: Novel Radioligands and (Pre-)Clinical Insights since 2016

by Susann Schröder, Matthias Scheunemann, Barbara Wenzel and Peter Brust

Int. J. Mol. Sci. 2021, 22(8), 3832; https://doi.org/10.3390/ijms22083832 - 7 Apr 2021

Cited by 4 | Viewed by 3000

Abstract

Cyclic nucleotide phosphodiesterases (PDEs) represent one of the key targets in the research field of intracellular signaling related to the second messenger molecules cyclic adenosine monophosphate (cAMP) and/or cyclic guanosine monophosphate (cGMP). Hence, non-invasive imaging of this enzyme class by positron emission tomography [...] Read more.

Cyclic nucleotide phosphodiesterases (PDEs) represent one of the key targets in the research field of intracellular signaling related to the second messenger molecules cyclic adenosine monophosphate (cAMP) and/or cyclic guanosine monophosphate (cGMP). Hence, non-invasive imaging of this enzyme class by positron emission tomography (PET) using appropriate isoform-selective PDE radioligands is gaining importance. This methodology enables the in vivo diagnosis and staging of numerous diseases associated with altered PDE density or activity in the periphery and the central nervous system as well as the translational evaluation of novel PDE inhibitors as therapeutics. In this follow-up review, we summarize the efforts in the development of novel PDE radioligands and highlight (pre-)clinical insights from PET studies using already known PDE radioligands since 2016. Full article

(This article belongs to the Special Issue Role of Phosphodiesterase in Biology and Pathology)

► Show Figures

Figure 1

35 pages, 484 KiB

Open AccessReview

Phosphodiesterase Inhibitors in Acute Lung Injury: What Are the Perspectives?

by Daniela Mokra and Juraj Mokry

Int. J. Mol. Sci. 2021, 22(4), 1929; https://doi.org/10.3390/ijms22041929 - 16 Feb 2021

Cited by 30 | Viewed by 4122

Abstract

Despite progress in understanding the pathophysiology of acute lung damage, currently approved treatment possibilities are limited to lung-protective ventilation, prone positioning, and supportive interventions. Various pharmacological approaches have also been tested, with neuromuscular blockers and corticosteroids considered as the most promising. However, inhibitors [...] Read more.

Despite progress in understanding the pathophysiology of acute lung damage, currently approved treatment possibilities are limited to lung-protective ventilation, prone positioning, and supportive interventions. Various pharmacological approaches have also been tested, with neuromuscular blockers and corticosteroids considered as the most promising. However, inhibitors of phosphodiesterases (PDEs) also exert a broad spectrum of favorable effects potentially beneficial in acute lung damage. This article reviews pharmacological action and therapeutical potential of nonselective and selective PDE inhibitors and summarizes the results from available studies focused on the use of PDE inhibitors in animal models and clinical studies, including their adverse effects. The data suggest that xanthines as representatives of nonselective PDE inhibitors may reduce acute lung damage, and decrease mortality and length of hospital stay. Various (selective) PDE3, PDE4, and PDE5 inhibitors have also demonstrated stabilization of the pulmonary epithelial–endothelial barrier and reduction the sepsis- and inflammation-increased microvascular permeability, and suppression of the production of inflammatory mediators, which finally resulted in improved oxygenation and ventilatory parameters. However, the current lack of sufficient clinical evidence limits their recommendation for a broader use. A separate chapter focuses on involvement of cyclic adenosine monophosphate (cAMP) and PDE-related changes in its metabolism in association with coronavirus disease 2019 (COVID-19). The chapter illuminates perspectives of the use of PDE inhibitors as an add-on treatment based on actual experimental and clinical trials with preliminary data suggesting their potential benefit. Full article

(This article belongs to the Special Issue Role of Phosphodiesterase in Biology and Pathology)

26 pages, 347 KiB

Open AccessReview

Role of Phosphodiesterase in the Biology and Pathology of Diabetes

by Agnieszka Kilanowska and Agnieszka Ziółkowska

Int. J. Mol. Sci. 2020, 21(21), 8244; https://doi.org/10.3390/ijms21218244 - 3 Nov 2020

Cited by 22 | Viewed by 5223

Abstract

Glucose metabolism is the initiator of a large number of molecular secretory processes in β cells. Cyclic nucleotides as a second messenger are the main physiological regulators of these processes and are functionally divided into compartments in pancreatic cells. Their intracellular concentration is [...] Read more.

Glucose metabolism is the initiator of a large number of molecular secretory processes in β cells. Cyclic nucleotides as a second messenger are the main physiological regulators of these processes and are functionally divided into compartments in pancreatic cells. Their intracellular concentration is limited by hydrolysis led by one or more phosphodiesterase (PDE) isoenzymes. Literature data confirmed multiple expressions of PDEs subtypes, but the specific roles of each in pancreatic β-cell function, particularly in humans, are still unclear. Isoforms present in the pancreas are also found in various tissues of the body. Normoglycemia and its strict control are supported by the appropriate release of insulin from the pancreas and the action of insulin in peripheral tissues, including processes related to homeostasis, the regulation of which is based on the PDE- cyclic AMP (cAMP) signaling pathway. The challenge in developing a therapeutic solution based on GSIS (glucose-stimulated insulin secretion) enhancers targeted at PDEs is the selective inhibition of their activity only within β cells. Undeniably, PDEs inhibitors have therapeutic potential, but some of them are burdened with certain adverse effects. Therefore, the chance to use knowledge in this field for diabetes treatment has been postulated for a long time. Full article

(This article belongs to the Special Issue Role of Phosphodiesterase in Biology and Pathology)

18 pages, 1685 KiB

Open AccessReview

Advances, Perspectives and Potential Engineering Strategies of Light-Gated Phosphodiesterases for Optogenetic Applications

by Yuehui Tian, Shang Yang and Shiqiang Gao

Int. J. Mol. Sci. 2020, 21(20), 7544; https://doi.org/10.3390/ijms21207544 - 13 Oct 2020

Cited by 5 | Viewed by 3507

Abstract

The second messengers, cyclic adenosine 3′-5′-monophosphate (cAMP) and cyclic guanosine 3′-5′-monophosphate (cGMP), play important roles in many animal cells by regulating intracellular signaling pathways and modulating cell physiology. Environmental cues like temperature, light, and chemical compounds can stimulate cell surface receptors and trigger [...] Read more.

The second messengers, cyclic adenosine 3′-5′-monophosphate (cAMP) and cyclic guanosine 3′-5′-monophosphate (cGMP), play important roles in many animal cells by regulating intracellular signaling pathways and modulating cell physiology. Environmental cues like temperature, light, and chemical compounds can stimulate cell surface receptors and trigger the generation of second messengers and the following regulations. The spread of cAMP and cGMP is further shaped by cyclic nucleotide phosphodiesterases (PDEs) for orchestration of intracellular microdomain signaling. However, localized intracellular cAMP and cGMP signaling requires further investigation. Optogenetic manipulation of cAMP and cGMP offers new opportunities for spatio-temporally precise study of their signaling mechanism. Light-gated nucleotide cyclases are well developed and applied for cAMP/cGMP manipulation. Recently discovered rhodopsin phosphodiesterase genes from protists established a new and direct biological connection between light and PDEs. Light-regulated PDEs are under development, and of demand to complete the toolkit for cAMP/cGMP manipulation. In this review, we summarize the state of the art, pros and cons of artificial and natural light-regulated PDEs, and discuss potential new strategies of developing light-gated PDEs for optogenetic manipulation. Full article

(This article belongs to the Special Issue Role of Phosphodiesterase in Biology and Pathology)

► Show Figures

Figure 1

29 pages, 2566 KiB

Open AccessReview

Therapeutic Implications for PDE2 and cGMP/cAMP Mediated Crosstalk in Cardiovascular Diseases

by Mirna S. Sadek, Eleder Cachorro, Ali El-Armouche and Susanne Kämmerer

Int. J. Mol. Sci. 2020, 21(20), 7462; https://doi.org/10.3390/ijms21207462 - 10 Oct 2020

Cited by 29 | Viewed by 7993

Abstract

Phosphodiesterases (PDEs) are the principal superfamily of enzymes responsible for degrading the secondary messengers 3′,5′-cyclic nucleotides cAMP and cGMP. Their refined subcellular localization and substrate specificity contribute to finely regulate cAMP/cGMP gradients in various cellular microdomains. Redistribution of multiple signal compartmentalization components is [...] Read more.

Phosphodiesterases (PDEs) are the principal superfamily of enzymes responsible for degrading the secondary messengers 3′,5′-cyclic nucleotides cAMP and cGMP. Their refined subcellular localization and substrate specificity contribute to finely regulate cAMP/cGMP gradients in various cellular microdomains. Redistribution of multiple signal compartmentalization components is often perceived under pathological conditions. Thereby PDEs have long been pursued as therapeutic targets in diverse disease conditions including neurological, metabolic, cancer and autoimmune disorders in addition to numerous cardiovascular diseases (CVDs). PDE2 is a unique member of the broad family of PDEs. In addition to its capability to hydrolyze both cAMP and cGMP, PDE2 is the sole isoform that may be allosterically activated by cGMP increasing its cAMP hydrolyzing activity. Within the cardiovascular system, PDE2 serves as an integral regulator for the crosstalk between cAMP/cGMP pathways and thereby may couple chronically adverse augmented cAMP signaling with cardioprotective cGMP signaling. This review provides a comprehensive overview of PDE2 regulatory functions in multiple cellular components within the cardiovascular system and also within various subcellular microdomains. Implications for PDE2- mediated crosstalk mechanisms in diverse cardiovascular pathologies are discussed highlighting the prospective use of PDE2 as a potential therapeutic target in cardiovascular disorders. Full article

(This article belongs to the Special Issue Role of Phosphodiesterase in Biology and Pathology)

► Show Figures

Figure 1

28 pages, 4172 KiB

Open AccessReview

Phosphodiesterases in the Liver as Potential Therapeutic Targets of Cirrhotic Portal Hypertension

by Wolfgang Kreisel, Denise Schaffner, Adhara Lazaro, Jonel Trebicka, Irmgard Merfort, Annette Schmitt-Graeff and Peter Deibert

Int. J. Mol. Sci. 2020, 21(17), 6223; https://doi.org/10.3390/ijms21176223 - 28 Aug 2020

Cited by 9 | Viewed by 4399

Abstract

Liver cirrhosis is a frequent condition with high impact on patients’ life expectancy and health care systems. Cirrhotic portal hypertension (PH) gradually develops with deteriorating liver function and can lead to life-threatening complications. Other than an increase in intrahepatic flow resistance due to [...] Read more.

Liver cirrhosis is a frequent condition with high impact on patients’ life expectancy and health care systems. Cirrhotic portal hypertension (PH) gradually develops with deteriorating liver function and can lead to life-threatening complications. Other than an increase in intrahepatic flow resistance due to morphological remodeling of the organ, a functional dysregulation of the sinusoids, the smallest functional units of liver vasculature, plays a pivotal role. Vascular tone is primarily regulated by the nitric oxide-cyclic guanosine monophosphate (NO-cGMP) pathway, wherein soluble guanylate cyclase (sGC) and phosphodiesterase-5 (PDE-5) are key enzymes. Recent data showed characteristic alterations in the expression of these regulatory enzymes or metabolite levels in liver cirrhosis. Additionally, a disturbed zonation of the components of this pathway along the sinusoids was detected. This review describes current knowledge of the pathophysiology of PH with focus on the enzymes regulating cGMP availability, i.e., sGC and PDE-5. The results have primarily been obtained in animal models of liver cirrhosis. However, clinical and histochemical data suggest that the new biochemical model we propose can be applied to human liver cirrhosis. The role of PDE-5 as potential target for medical therapy of PH is discussed. Full article

(This article belongs to the Special Issue Role of Phosphodiesterase in Biology and Pathology)

► Show Figures

Figure 1

15 pages, 263 KiB

Open AccessReview

Role of Phosphodiesterase 7 (PDE7) in T Cell Activity. Effects of Selective PDE7 Inhibitors and Dual PDE4/7 Inhibitors on T Cell Functions

by Marianna Szczypka

Int. J. Mol. Sci. 2020, 21(17), 6118; https://doi.org/10.3390/ijms21176118 - 25 Aug 2020

Cited by 17 | Viewed by 3639

Abstract

Phosphodiesterase 7 (PDE7), a cAMP-specific PDE family, insensitive to rolipram, is present in many immune cells, including T lymphocytes. Two genes of PDE7 have been identified: PDE7A and PDE7B with three or four splice variants, respectively. Both PDE7A and PDE7B are expressed in [...] Read more.

Phosphodiesterase 7 (PDE7), a cAMP-specific PDE family, insensitive to rolipram, is present in many immune cells, including T lymphocytes. Two genes of PDE7 have been identified: PDE7A and PDE7B with three or four splice variants, respectively. Both PDE7A and PDE7B are expressed in T cells, and the predominant splice variant in these cells is PDE7A1. PDE7 is one of several PDE families that terminates biological functions of cAMP—a major regulating intracellular factor. However, the precise role of PDE7 in T cell activation and function is still ambiguous. Some authors reported its crucial role in T cell activation, while according to other studies PDE7 activity was not pivotal to T cells. Several studies showed that inhibition of PDE7 by its selective or dual PDE4/7 inhibitors suppresses T cell activity, and consequently T-mediated immune response. Taken together, it seems quite likely that simultaneous inhibition of PDE4 and PDE7 by dual PDE4/7 inhibitors or a combination of selective PDE4 and PDE7 remains the most interesting therapeutic target for the treatment of some immune-related disorders, such as autoimmune diseases, or selected respiratory diseases. An interesting direction of future studies could also be using a combination of selective PDE7 and PDE3 inhibitors. Full article

(This article belongs to the Special Issue Role of Phosphodiesterase in Biology and Pathology)

11 pages, 561 KiB

Open AccessReview

Phosphodiesterase Inhibitors: Could They Be Beneficial for the Treatment of COVID-19?

by Mauro Giorgi, Silvia Cardarelli, Federica Ragusa, Michele Saliola, Stefano Biagioni, Giancarlo Poiana, Fabio Naro and Mara Massimi

Int. J. Mol. Sci. 2020, 21(15), 5338; https://doi.org/10.3390/ijms21155338 - 27 Jul 2020

Cited by 35 | Viewed by 12627

Abstract

In March 2020, the World Health Organization declared the severe acute respiratory syndrome corona virus 2 (SARS-CoV2) infection to be a pandemic disease. SARS-CoV2 was first identified in China and, despite the restrictive measures adopted, the epidemic has spread globally, becoming a pandemic [...] Read more.

In March 2020, the World Health Organization declared the severe acute respiratory syndrome corona virus 2 (SARS-CoV2) infection to be a pandemic disease. SARS-CoV2 was first identified in China and, despite the restrictive measures adopted, the epidemic has spread globally, becoming a pandemic in a very short time. Though there is growing knowledge of the SARS-CoV2 infection and its clinical manifestations, an effective cure to limit its acute symptoms and its severe complications has not yet been found. Given the worldwide health and economic emergency issues accompanying this pandemic, there is an absolute urgency to identify effective treatments and reduce the post infection outcomes. In this context, phosphodiesterases (PDEs), evolutionarily conserved cyclic nucleotide (cAMP/cGMP) hydrolyzing enzymes, could emerge as new potential targets. Given their extended distribution and modulating role in nearly all organs and cellular environments, a large number of drugs (PDE inhibitors) have been developed to control the specific functions of each PDE family. These PDE inhibitors have already been used in the treatment of pathologies that show clinical signs and symptoms completely or partially overlapping with post-COVID-19 conditions (e.g., thrombosis, inflammation, fibrosis), while new PDE-selective or pan-selective inhibitors are currently under study. This review discusses the state of the art of the different pathologies currently treated with phosphodiesterase inhibitors, highlighting the numerous similarities with the disorders linked to SARS-CoV2 infection, to support the hypothesis that PDE inhibitors, alone or in combination with other drugs, could be beneficial for the treatment of COVID-19. Full article

(This article belongs to the Special Issue Role of Phosphodiesterase in Biology and Pathology)

► Show Figures

Figure 1

Journal Menu

Journal Browser

Role of Phosphodiesterase in Biology and Pathology 2.0

Share This Special Issue

Special Issue Editors

Special Issue Information

Keywords

Benefits of Publishing in a Special Issue

Related Special Issue

Published Papers (26 papers)

Editorial

Research

Review

Further Information

Guidelines

MDPI Initiatives

Follow MDPI