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Dear Colleagues,

The impact of cyclic nucleotides such as cAMP or cGMP on normal and cancer cell growth has long been recognized. However, downstream signaling pathways that are either activated or suppressed by cyclic nucleotides that mediate growth regulation or are essential for growth have not been well defined. Multiple lines of evidence suggest that cyclic nucleotides can suppress key oncogenic signaling pathways resulting from mutations in various pathway components, including RAS and β-catenin. However, no anticancer drugs have been approved, or are on the horizon, that target cyclic nucleotide levels despite numerous publications reporting that the expression of various cyclic nucleotide phosphodiesterases is altered during malignant progression. This Special Issue will highlight publications from investigators in the cancer field studying cyclic nucleotides and phosphodiesterases and exchange information essential for target validation and pathway elucidation. The goal is to accelerate the discovery and development of new anticancer drugs that target cyclic nucleotide signaling pathways involved in cancer initiation, promotion, or progression.

Prof. Dr. Gary A. Piazza
Guest Editor

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Keywords

Cyclic AMP
Cyclic GMP
Phosphodiesterase
Cancer
Inhibitor
Adenylate cyclase
Guanylate cyclase
PDE10
PDE5

Published Papers (2 papers)

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Research

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14 pages, 2388 KiB

Open AccessArticle

Age Impairs Soluble Guanylyl Cyclase Function in Mouse Mesenteric Arteries

by Cheng Zhong, Minze Xu, Sengül Boral, Holger Summer, Falk-Bach Lichtenberger, Cem Erdoğan, Maik Gollasch, Stefan Golz, Pontus B. Persson, Johanna Schleifenbaum, Andreas Patzak and Pratik H. Khedkar

Int. J. Mol. Sci. 2021, 22(21), 11412; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms222111412 - 22 Oct 2021

Cited by 11 | Viewed by 2771

Abstract

Endothelial dysfunction (ED) comes with age, even without overt vessel damage such as that which occurs in atherosclerosis and diabetic vasculopathy. We hypothesized that aging would affect the downstream signalling of the endothelial nitric oxide (NO) system in the vascular smooth muscle (VSM). With this in mind, resistance mesenteric arteries were isolated from 13-week (juvenile) and 40-week-old (aged) mice and tested under isometric conditions using wire myography. Acetylcholine (ACh)-induced relaxation was reduced in aged as compared to juvenile vessels. Pretreatment with L-NAME, which inhibits nitrix oxide synthases (NOS), decreased ACh-mediated vasorelaxation, whereby differences in vasorelaxation between groups disappeared. Endothelium-independent vasorelaxation by the NO donor sodium nitroprusside (SNP) was similar in both groups; however, SNP bolus application (10⁻⁶ mol L⁻¹) as well as soluble guanylyl cyclase (sGC) activation by runcaciguat (10⁻⁶ mol L⁻¹) caused faster responses in juvenile vessels. This was accompanied by higher cGMP concentrations and a stronger response to the PDE5 inhibitor sildenafil in juvenile vessels. Mesenteric arteries and aortas did not reveal apparent histological differences between groups (van Gieson staining). The mRNA expression of the α1 and α2 subunits of sGC was lower in aged animals, as was PDE5 mRNA expression. In conclusion, vasorelaxation is compromised at an early age in mice even in the absence of histopathological alterations. Vascular smooth muscle sGC is a key element in aged vessel dysfunction. Full article

(This article belongs to the Special Issue Cyclic Nucleotides, Phosphodiesterases, and Cancer)

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Review

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33 pages, 5008 KiB

Open AccessReview

Dual Activation of Phosphodiesterase 3 and 4 Regulates Basal Cardiac Pacemaker Function and Beyond

by Tatiana M. Vinogradova and Edward G. Lakatta

Int. J. Mol. Sci. 2021, 22(16), 8414; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22168414 - 05 Aug 2021

Cited by 9 | Viewed by 2328

Abstract

The sinoatrial (SA) node is the physiological pacemaker of the heart, and resting heart rate in humans is a well-known risk factor for cardiovascular disease and mortality. Consequently, the mechanisms of initiating and regulating the normal spontaneous SA node beating rate are of vital importance. Spontaneous firing of the SA node is generated within sinoatrial nodal cells (SANC), which is regulated by the coupled-clock pacemaker system. Normal spontaneous beating of SANC is driven by a high level of cAMP-mediated PKA-dependent protein phosphorylation, which rely on the balance between high basal cAMP production by adenylyl cyclases and high basal cAMP degradation by cyclic nucleotide phosphodiesterases (PDEs). This diverse class of enzymes includes 11 families and PDE3 and PDE4 families dominate in both the SA node and cardiac myocardium, degrading cAMP and, consequently, regulating basal cardiac pacemaker function and excitation-contraction coupling. In this review, we will demonstrate similarities between expression, distribution, and colocalization of various PDE subtypes in SANC and cardiac myocytes of different species, including humans, focusing on PDE3 and PDE4. Here, we will describe specific targets of the coupled-clock pacemaker system modulated by dual PDE3 + PDE4 activation and provide evidence that concurrent activation of PDE3 + PDE4, operating in a synergistic manner, regulates the basal cardiac pacemaker function and provides control over normal spontaneous beating of SANCs through (PDE3 + PDE4)-dependent modulation of local subsarcolemmal Ca²⁺ releases (LCRs). Full article

(This article belongs to the Special Issue Cyclic Nucleotides, Phosphodiesterases, and Cancer)

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