Role of inhibitors of histone deacetylase and DNA-methyltransferase and activator of sirtuin-1 on the NO-sGC-cGMP pathway in the bladder, urethra and prostate under physiological and pathological conditions (obesity and cystitis).

• Grant number: 19/19490-4
• Support Opportunities: Scholarships in Brazil - Post-Doctorate
• Effective date (Start): October 01, 2019
• Effective date (End): September 30, 2023
• Field of knowledge: Biological Sciences - Pharmacology - Autonomic Pharmacology
• Principal Investigator: Fabíola Taufic Monica Iglesias
• Grantee: Ana Carolina Ghezzi Beghini
• Host Institution: Faculdade de Ciências Médicas (FCM). Universidade Estadual de Campinas (UNICAMP). Campinas , SP, Brazil
• Associated research grant: 17/15175-1 - Modulation of soluble guanylate cyclase and the intracellular levels of cyclic nucleotides in the lower urinary tract and prostate, AP.TEM
• Associated scholarship(s): 21/14495-8 - Role of histone deacetylase type 11 (HDAC11) in the inflammatory modulation of the prostate in LPS-induced prostatitis, BE.EP.PD

Abstract

DNA methylation, posttranslational modifications of histone such as acetylation (HA) and deacetylation (HDAC) and non-coding RNA are the major epigenetic mechanisms that lead to alteration of gene expression. Regarding the role of epigenetic-regulation of the NO-sGC pathway, the eNOS (NOS-3) has been examined. The eNOS proximal promoter is hypomethylated and hyperacetylated in human endothelial cells, but is heavily methylated in human vascular smooth muscle cells, thus suggesting that epigenetic mechanisms are involved in the endothelial-specific expression of eNOS. In vascular smooth muscle cells, treatment with inhibitors of HDAC and DNA-methyltransferase increased eNOS expression. In isolated cells from aorta the addition of a pro-inflammatory mixture reduced the expression of sGC beta-1 possibly due to a decrease on the transcriptional activity of the promoter region sGC beta-1. Recently, white adipocytes treated with TNF-alpha the levels of sGC beta1 and the cGMP were reduced in a mechanism dependent on the activation of NF-kB. While in the urogenital organs from obese or cyclophosphamide (CYP)-induced cystitis animals the hypercontractility state seen in the bladder/urethra and prostate could be due to sGC subunits degradation that lead to lower cGMP levels mainly due to greter levels of reactive oxygen species, this project is aimed to evaluate the methylation levels of the promoter regions of the eNOS, nNOS and sGC genes and whether drugs that inhibit histone deacetylase (SAHA) or DNA-methyltransferase (5-azacitydine) or an activator of sirutin-1, a class III histone deacetylase (GSK2245840 ou SRT2104) are efficacious in reverting the overactive and inflammatory state seen in the bladder with CYP-induced cystitis or in prostate, bladder and urethra from obese mice.

Scientific publications

(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. (19/19490-4, 18/09765-3, 17/15175-1, 18/05956-9, 18/21880-2)