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 type: Scholarships in Brazil - Scientific Initiation
• Effective date (Start): June 01, 2022
• Effective date (End): May 31, 2023
• Field of knowledge: Biological Sciences - Pharmacology - Cardiorenal Pharmacology
• Principal researcher: Rita de Cassia Aleixo Tostes Passaglia
• Grantee: Anna Flavia Rodrigues Lima
• Home 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

Abstract

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 result 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 antioxidant genes transcription. 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 the obesity development. In addition, for functional studies of PVAT, we will perform vascular reactivity assays in thoracic aorta and molecular assays to clarify mechanisms.