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Project

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)

Funder: São Paulo Research Foundation

Funding period
0
Funding amount
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.
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System

Categories
  • FOR (ANZSRC)

    0604 Genetics

  • RCDC

    Prostate Cancer

  • RCDC

    Obesity

  • RCDC

    Cancer

  • RCDC

    Genetics

  • RCDC

    Urologic Diseases

  • HRCS RAC

    2.1 Biological and endogenous factors

  • Health Research Areas

    Biomedical

  • Broad Research Areas

    Basic Science