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The role of beclin 1-dependent autophagy in aldosterone-induced perivascular adipose tissue dysfunction

Grant number: 22/06639-2
Support Opportunities:Scholarships abroad - Research Internship - Post-doctor
Effective date (Start): September 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:Rafael Menezes da Costa
Supervisor: Thiago Bruder do Nascimento
Host Institution: Faculdade de Medicina de Ribeirão Preto (FMRP). Universidade de São Paulo (USP). Ribeirão Preto , SP, Brazil
Research place: University of Pittsburgh (Pitt), United States  
Associated to the scholarship:21/08847-9 - Contribution of autophagic processes in perivascular adipose tissue hyperinflammation associated with metabolic syndrome, BP.PD

Abstract

Perivascular adipose tissue (PVAT) is recognized as an endocrine organ that releases a wide variety of adipokines, which negatively modulate vascular contraction. In comorbidities and cardiometabolic diseases, changes in PVAT morphology and function are observed. Aldosterone, a mineralocorticoid hormone that increases cardiovascular risk, induces PVAT dysfunction. The mechanisms that justify such events are associated with inflammation, oxidative stress and the exacerbated release of hormones and vasoconstrictor peptides by the PVAT. Autophagic processes are of extreme importance for inflammatory tolerance. Autophagy is an essential process consisting of the degradation and recycling of cellular components. Beclin 1, a key regulator of autophagy, is important for the labeling and localization of autophagic proteins, in addition to being involved in the nucleation and fusion step of the autophagosome to lysosomes. We questioned whether aldosterone modulates Beclin 1 activity and, consequently, autophagy and inflammation in the PVAT. We hypothesized that aldosterone reduces Beclin 1 activity, decreasing autophagy, and promoting inflammation and PVAT dysfunction. We expect that pharmacological activation of Beclin 1 and gain of Beclin 1-dependent autophagic function by experimental genetic manipulation will prevent aldosterone-induced effects. To test our hypothesis, we will use C57BL/6 mice and Becn1F121A knock-in mice (B6.129(Cg)-Becn1tm2.1Blev/J) infused with aldosterone for 14 days. In addition, C57BL/6 mice infused with aldosterone will be treated with Beclin 1 activator peptide (TB-peptide). Vascular reactivity and histological assays will be performed to assess the function and structure of PVAT, respectively. Autophagic flux proteins and pro-inflammatory cytokines will be evaluated by molecular assays. (AU)

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