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Contribution of endothelin-1 in perivascular adipose tissue dysfunction in obese mice: involvement of transcriptional factor Nrf2 and kinase GSK-3B

Grant number: 22/04846-0
Support Opportunities:Scholarships in Brazil - Scientific Initiation
Effective date (Start): June 01, 2022
Effective date (End): August 31, 2023
Field of knowledge:Biological Sciences - Pharmacology - Cardiorenal Pharmacology
Principal Investigator:Rita de Cassia Aleixo Tostes Passaglia
Grantee:Anna Flavia Rodrigues Lima
Host Institution: Faculdade de Medicina de Ribeirão Preto (FMRP). Universidade de São Paulo (USP). Ribeirão Preto , SP, Brazil
Associated research grant:13/08216-2 - CRID - Center for Research in Inflammatory Diseases, AP.CEPID


Obesity is a multifactorial chronic pathophysiological condition characterized by excess adipose tissue in relation to lean mass, a consequence of a sedentary lifestyle and inadequate diet, which results in a greater propensity to develop cardiovascular diseases. Perivascular adipose tissue (PVAT) regulates vascular tone under physiological conditions. However, in obesity, structural and functional changes occur in this tissue that results in oxidative stress, favoring the release of vasoconstrictor and pro-inflammatory substances. The production of reactive oxygen species (ROS) in the vasculature is mediated by different stimuli, including endothelin-1 (ET-1), a peptide that promotes a balance between vasoconstrictor and vasodilator responses. Among the intracellular signaling pathways capable of neutralizing ROS, the nuclear transcriptional factor E2 related to factor 2 (Nrf2) promotes the transcription of the antioxidant gene. Nrf2 is regulated by the protein glycogen synthase kinase-3B (GSK-3B), which when phosphorylated in Tyr216 negatively regulates the activity of Nrf2. This project will test the hypothesis that in obesity there is an increase in the production of ET-1 in PVAT and that ET-1, by phosphorylating GSK-3B in Tyr216, negatively regulates Nrf2, increasing the generation of ROS and promoting dysfunction of this tissue. To test our hypothesis, we will use C57BL/6J male mice fed a standard or high-fat diet for obesity development. In addition, for functional studies of PVAT, we will perform vascular reactivity assays in the thoracic aorta and molecular assays to clarify mechanisms.(AU)

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