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Modulation of soluble guanylate cyclase and the intracellular levels of cyclic nucleotides in the lower urinary tract and prostate

Abstract

Activation of soluble Guanylate Cyclase (sGC) enzyme expressed in bladder, urethra and prostate smooth muscles induces tissue relaxations by elevating cyclic GMP levels. We have shown that sGC enzyme is found in an oxidized/degraded state in Obesity, Aging and Inflammation (cystitis) conditions, hence producing reduced cGMP levels, which may explain the enhanced contractility of the lower urinary tract smooth muscles. This project was divided into five independent sub-projects, all addressing several unanswered issues regarding the sGC modulation and cGMP production in the bladder, urethral and prostatic disorders. Main Methods: animal models of obesity, aging and inflammation (cystitis) along with cell cultures of detrusor and prostate smooth muscles. Human tissues will also be used according appropriate ethical consents. Our study will mostly consist of in vivo (cystometry) and reactivity assays, together with RT-PCR, western blotting, ELISA, immunohistochemistry and gene silencing techniques. Subproject #1:"Multidrug resistance proteins" (MRP4, MRP5 and MRP8) located in cell membranes act to pump the cyclic nucleotides outside the cell. We propose to examine the localization and expressions of these efflux transporters, and to evaluate its influence on the sGC-cGMP downstream proteins. We have also thought that cGMP present in the extracellular space may be converted sequentially to GTP, GDP, GMP and guanosine, which in turn would act extracellularly in cell membrane controlling the smooth muscle tone. Therefore, we also aim to characterize the effects of GTP, GDP, GMP and guanosine in bladder, urethra and prostates. Subproject #2: Enhanced reactive-oxygen levels (ROS) levels inactivate NO and degrade sGC, which may account for the hyper contractility state of the lower urinary tract in diseased states. Our proposal here is to identify the NOX (NADPH oxidase) isoforms, and to investigate the modulatory role exerted by NOX1/4 inhibition with GKT137831 using both functional responses and expressions of sGC itself and its downstream signaling proteins. Subproject #3: In breast cancer cell lines, epigenetic mechanisms contribute to sGC-cGMP downregulation, thus favoring the proliferative state. Therefore, we will examine the methylation and acetylation state of sGC gene (in comparison with eNOS and nNOS), and evaluate whether the epigenetic inhibitors vorinostat, 5-azacitidina and GSK2245840 improve the overactive state by rescuing the sGC-cGMP-PKG pathway. Subproject #4: Hydrogen sulfide (H2S) favors the reduced state of sGC (Fe2+), thus enhancing the NO-mediated responses. Our proposals here are to identify the expressions of H2S-producing enzymes (CBS, CSE and 3-MST), and to investigate the modulation of sGC and its downstream signaling proteins by H2S. Subproject #5: Toll-like receptor 4 (TLR4) and its intracellular signaling (MyD88, TRIAP, TRIF, TRAMP, IFR-3 and NF-kB) lead to generation of inflammatory mediators and increased oxidative stress, resulting in sGC degradation. This project aims to investigate the role of TLR4 and its downstream signaling in triggering bladder dysfunction. The cross talk between TLR4 and sGC will be explored here through the use of TLR4-/- mice and of pharmacological strategies of TLR4 blockade. Why is our group suitable for answering these issues? Our group was one of the first in Brazil to work with erectile dysfunction, and contributed to several publications and to acquisition of knowledge/competences (PhD's and Postdoctoral). During the last 10 years; we have acquired a large experience on lower urinary tract diseases, particularly with the modulation of sGC-cGMP signaling. As a result, recently, we had a review accepted for publication at "Nature re"nature reviews in urology". Therefore, we have the expertise to solve unanswered and relevant questions about the regulation of sGC-cGMP in the lower urinary tract organs in the health and pathological state. (AU)

Scientific publications (23)
(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)
PASSOS, GABRIELA REOLON; GHEZZI, ANA CAROLINA; ANTUNES, EDSON; DE OLIVEIRA, MARIANA GONCALVES; MONICA, FABIOLA ZAKIA. The Role of Periprostatic Adipose Tissue on Prostate Function in Vascular-Related Disorders. FRONTIERS IN PHARMACOLOGY, v. 12, FEB 12 2021. Web of Science Citations: 0.
JUSTO, ALBERTO FERNANDO O.; DE OLIVEIRA, MARIANA G.; CALMASINI, FABIANO B.; ALEXANDRE, EDUARDO C.; BERTOLLOTTO, GABRIELA MARIA; JACINTHO, FELIPE FERNANDES; ANTUNES, EDSON; MONICA, FABIOLA Z. Preserved activity of soluble guanylate cyclase (sGC) in iliac artery from middle-aged rats: Role of sGC modulators. NITRIC OXIDE-BIOLOGY AND CHEMISTRY, v. 106, p. 9-16, JAN 1 2021. Web of Science Citations: 0.
PINHEIRO-TORRES, A. S.; FERREIRA-DUARTE, A. P.; TAKESHITA, W. M.; GUSHIKEN, V. O.; RONCALHO-BUCK, I. A.; ANHE, G. F.; ANTUNES, E.; DESOUZA, I. A. Airways exposure of bacterial superantigen SEB enhances bone marrow eosinophil population and facilitates its egress to blood and lung tissue. Life Sciences, v. 264, JAN 1 2021. Web of Science Citations: 0.
BRITTO-JUNIOR, JOSE; JACINTHO, FELIPE FERNANDES; CAMPOS, RAFAEL; ARAUJO PINHEIRO, DAVID HALEN; FIGUEIREDO MURARI, GUILHERME M.; DE SOUZA, VALERIA B.; SCHENKA, ANDRE A.; MONICA, FABIOLA Z.; MORENO, RONILSON AGNALDO; ANTUNES, EDSON; DE NUCCI, GILBERTO. The basal release of endothelium-derived catecholamines regulates the contractions of Chelonoidis carbonaria aorta caused by electrical-field stimulation. BIOLOGY OPEN, v. 10, n. 1 JAN 2021. Web of Science Citations: 1.
LESCANO, CAROLINE HONAISER; LEONARDI, GUILHERME; PORTUGAL TORRES, PEDRO HENRIQUE; AMARAL, TIAGO NARDI; DE FREITAS FILHO, LUIZ HENRIQUE; ANTUNES, EDSON; VICENTE, CRISTINA PONTES; ANHE, GABRIEL FORATO; MONICA, FABIOLA ZAKIA. The sodium-glucose cotransporter-2 (SGLT2) inhibitors synergize with nitric oxide and prostacyclin to reduce human platelet activation. Biochemical Pharmacology, v. 182, DEC 2020. Web of Science Citations: 0.
BRITTO-JUNIOR, JOSE; PINHEIRO, DAVID H. A.; JUSTO, ALBERTO F. O.; FIGUEIREDO MURARI, GUILHERME M.; CAMPOS, RAFAEL; MARIANO, V, FERNANDA; DE SOUZA, VALERIA B.; SCHENKA, ANDRE A.; MONICA, FABIOLA Z.; ANTUNES, EDSON; DE NUCCI, GILBERTO. Endothelium-derived dopamine modulates EFS-induced contractions of human umbilical vessels. PHARMACOLOGY RESEARCH & PERSPECTIVES, v. 8, n. 4 AUG 2020. Web of Science Citations: 0.
COLLACO, RITA DE CASSIA; HYSLOP, STEPHEN; ROCHA, THALITA; DORCE, VALQUIRIA A. C.; ROWAN, EDWARD G.; ANTUNES, EDSON. Neurotoxicity ofTityus bahiensis(brown scorpion) venom in sympathetic vas deferens preparations and neuronal cells. ARCHIVES OF TOXICOLOGY, v. 94, n. 9 JUN 2020. Web of Science Citations: 0.
DE ALMEIDA KIGUTI, LUIZ RICARDO; PACHECO, TAINA LOUISE; ANTUNES, EDSON; KEMPINAS, WILMA DE GRAVA. Lorcaserin Administration has Pro-Ejaculatory Effects in Rats via 5-HT2C Receptors Activation: A Putative Pharmacologic Strategy to Delayed Ejaculation?. Journal of Sexual Medicine, v. 17, n. 6, p. 1060-1071, JUN 2020. Web of Science Citations: 0.
NICOLETTI, ALINE DE SOUZA; PASSOS, GABRIELA REOLON; BERTOLLOTTO, GABRIELA MARIA; LESCANO, CAROLINE HONAISER; DE OLIVEIRA, MARIANA GONCALVES; ANTUNES, EDSON; MONICA, FABIOLA ZAKIA. Guanosine, a guanine-based nucleoside relaxed isolated corpus cavernosum from mice through cGMP accumulation. PURINERGIC SIGNALLING, v. 16, n. 2 MAY 2020. Web of Science Citations: 0.
DE OLIVEIRA, MARIANA G.; DE MEDEIROS, MATHEUS L.; TAVARES, EDITH B. G.; MONICA, FABIOLA Z.; ANTUNES, EDSON. Methylglyoxal, a Reactive Glucose Metabolite, Induces Bladder Overactivity in Addition to Inflammation in Mice. FRONTIERS IN PHYSIOLOGY, v. 11, APR 3 2020. Web of Science Citations: 0.
MEDEIROS, MATHEUS L.; DE OLIVEIRA, MARIANA G.; TAVARES, EDITH G.; MELLO, GLAUCIA C.; ANHE, GABRIEL F.; MONICA, FABIOLA Z.; ANTUNES, EDSON. Long-term methylglyoxal intake aggravates murine Th2-mediated airway eosinophil infiltration. International Immunopharmacology, v. 81, APR 2020. Web of Science Citations: 0.
ALEXANDRE, EDUARDO C.; CAO, NAILONG; MIZOGUCHI, SHINSUKE; SAITO, TETSUICHI; KUROBE, MASAHIRO; GOTOH, DAISUKE; OKORIE, MERI; IGARASHI, TARO; ANTUNES, EDSON; YOSHIMURA, NAOKI. Urethral dysfunction in a rat model of chemically induced prostatic inflammation: potential involvement of the MRP5 pump. AMERICAN JOURNAL OF PHYSIOLOGY-RENAL PHYSIOLOGY, v. 318, n. 3, p. F754-F762, MAR 2020. Web of Science Citations: 0.
BRITTO-JUNIOR, JOSE; JACINTHO, FELIPE FERNANDES; FIGUEIREDO MURARI, GUILHERME M.; CAMPOS, RAFAEL; MORENO, RONILSON AGNALDO; ANTUNES, EDSON; MONICA, FABIOLA Z.; DE NUCCI, GILBERTO. Electrical field stimulation induces endothelium-dependent contraction of human umbilical cord vessels. Life Sciences, v. 243, FEB 15 2020. Web of Science Citations: 0.
E-LACERDA, RODRIGO RODRIGUES; TEIXEIRA, CAIO JORDAO; BORDIN, SILVANA; ANTUNES, EDSON; ANHE, GABRIEL FORATO. Maternal Obesity in Mice Exacerbates the Allergic Inflammatory Response in the Airways of Male Offspring. NUTRIENTS, v. 11, n. 12 DEC 2019. Web of Science Citations: 0.
DE OLIVEIRA, MARIANA G.; ROJAS-MOSCOSO, JULIO ALEJANDRO; BERTOLLOTTO, GABRIELA M.; CANDIDO, TUANY Z.; KIGUTI, LUIZ RICARDO DE A.; PUPO, ANDRE S.; ANTUNES, EDSON; DE NUCCI, GILBERTO; MONICA, FABIOLA Z. Mirabegron elicits rat corpus cavernosum relaxation and increases in vivo erectile response. European Journal of Pharmacology, v. 858, SEP 5 2019. Web of Science Citations: 1.
COLLACO, RITA DE CASSIA O.; HYSLOP, STEPHEN; DORCE, VALQUIRIA A. C.; ANTUNES, EDSON; ROWAN, EDWARD G. Scorpion venom increases acetylcholine release by prolonging the duration of somatic nerve action potentials. Neuropharmacology, v. 153, p. 41-52, JUL 15 2019. Web of Science Citations: 0.
AKINAGA, JULIANA; ADOLFO GARCIA-SAINZ, J.; PUPO, ANDRE S. Updates in the function and regulation of alpha(1)-adrenoceptors. British Journal of Pharmacology, v. 176, n. 14, SI, p. 2343-2357, JUL 2019. Web of Science Citations: 3.
DE OLIVEIRA, MARIANA GONCALVES; ALEXANDRE, EDUARDO COSTA; BONILLA-BECERRA, SANDRA MILENA; BERTOLLOTTO, GABRIELA MARIA; OLIVEIRA JUSTO, ALBERTO FERNANDO; MONICA, FABIOLA ZAKIA; ANTUNES, EDSON. Autonomic dysregulation at multiple sites is implicated in age-associated underactive bladder in female mice. NEUROUROLOGY AND URODYNAMICS, v. 38, n. 5, p. 1212-1221, JUN 2019. Web of Science Citations: 0.
MUELLER, ANDRE; KIGUTI, LUIZ R. A.; SILVA, ERICK J. R.; PUPO, ANDRE S. Contractile Effects of Serotonin (5-HT) in the Rat Cauda Epididymis: Expression and Functional Characterization of 5-HT Receptors. Journal of Pharmacology and Experimental Therapeutics, v. 369, n. 1, p. 98-106, APR 1 2019. Web of Science Citations: 0.
DE OLIVEIRA, MARIANA G.; NASCIMENTO, DANIEL M.; ALEXANDRE, EDUARDO C.; BONILLA-BECERRA, SANDRA M.; ZAPPAROLI, ADRIANA; MONICA, FABIOLA Z.; ANTUNES, EDSON. Menthol ameliorates voiding dysfunction in types I and II diabetic mouse model. NEUROUROLOGY AND URODYNAMICS, v. 37, n. 8, p. 2510-2518, NOV 2018. Web of Science Citations: 4.
ALEXANDRE, EDUARDO C.; CALMASINI, FABIANO B.; SPONTON, AMANDA C. DA S.; DE OLIVEIRA, MARIANA G.; ANDRE, DIANA M.; SILVA, FABIO H.; DEBIN, MARIA ANDREIA; MONICA, FABIOLA Z.; ANTUNES, EDSON. Influence of the periprostatic adipose tissue in obesity-associated mouse urethral dysfunction and oxidative stress: Effect of resveratrol treatment. European Journal of Pharmacology, v. 836, p. 25-33, OCT 5 2018. Web of Science Citations: 0.
BERTOLLOTTO, GABRIELA MARIA; DE OLIVEIRA, MARIANA GONCALVES; ALEXANDRE, EDUARDO COSTA; CALMASINI, FABIANO BERALDI; PASSOS, GABRIELA REOLON; ANTUNES, EDSON; MONICA, FABIOLA ZAKIA. Inhibition of Multidrug Resistance Proteins by MK 571 Enhances Bladder, Prostate, and Urethra Relaxation through cAMP or cGMP Accumulation. Journal of Pharmacology and Experimental Therapeutics, v. 367, n. 1, p. 138-146, OCT 1 2018. Web of Science Citations: 2.
DE OLIVEIRA, MARIANA G.; MONICA, FABIOLA Z.; CALMASINI, FABIANO B.; ALEXANDRE, EDUARDO C.; TAVARES, EDITH B. G.; SOARES, ANTONIO G.; COSTA, SORAIA K. P.; ANTUNES, EDSON. Deletion or pharmacological blockade of TLR4 confers protection against cyclophosphamide-induced mouse cystitis. AMERICAN JOURNAL OF PHYSIOLOGY-RENAL PHYSIOLOGY, v. 315, n. 3, p. F460-F468, SEP 2018. Web of Science Citations: 4.

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