Endothelin-1 down-regulates nuclear factor erythroid 2-related factor-2 and contributes to perivascular adipose tissue dysfunction in obesity

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Lima, Anna Flavia R. ; Rodrigues, Daniel ; Machado, Mirele R. ; Oliveira-Neto, Jose Teles ; Bressan, Alecsander F. M. ; Pedersoli, Carina A. ; Alves, Juliano, V ; Silva-Neto, Julio A. ; Barros, Paula R. ; Dias, Thiago B. ; Garcia, Luis, V ; Bruder-Nascimento, Ariane ; Bruder-Nascimento, Thiago ; Carneiro, Fernando S. ; Osorio, Luiz ; Leiria, S. ; Tostes, Rita C. ; Costa, Rafael M.

• Document type: Journal article
• Source: Clinical Science; v. 138, n. 17, p. 17-pg., 2024-09-01.

Abstract

Perivascular adipose tissue (PVAT) negatively regulates vascular muscle contraction. However, in the context of obesity, the PVAT releases vasoconstrictor substances that detrimentally affect vascular function. A pivotal player in this scenario is the peptide endothelin-1 (ET-1), which induces oxidative stress and disrupts vascular function. The present study postulates that obesity augments ET-1 production in the PVAT, decreases the function of the nuclear factor erythroid 2-related factor-2 (Nrf2) transcription factor, further increasing reactive oxygen species (ROS) generation, culminating in PVAT dysfunction. Male C57BL/6 mice were fed either a standard or a high-fat diet for 16 weeks. Mice were also treated with saline or a daily dose of 100 mg <middle dot> kg-1 - 1 of the ETA and ETB receptor antagonist Bosentan, for 7 days. Vascular function was evaluated in thoracic aortic rings, with and without PVAT. Mechanistic studies utilized PVAT from all groups and cultured WT-1 mouse brown adipocytes. PVAT from obese mice exhibited increased ET-1 production, increased ECE1 and ETA gene expression, loss of the anticontractile effect, as well as increased ROS production, decreased Nrf2 activity, and downregulated expression of Nrf2-targeted antioxidant genes. PVAT of obese mice also exhibited increased expression of Tyr216-phosphorylated-GSK3 beta 216-phosphorylated-GSK3 beta and KEAP1, but not BACH1- negative Nrf2 regulators. Bosentan treatment reversed all these effects. Similarly, ET-1 increased ROS generation and decreased Nrf2 activity in brown adipocytes, events mitigated by BQ123 (ETA receptor antagonist). These findings place ET-1 as a major contributor to PVAT dysfunction in obesity and highlight that pharmacological control of ET-1 effects restores PVAT's cardiovascular protective role. (AU)

• FAPESP's process: 13/08216-2 - CRID - Center for Research in Inflammatory Diseases
• Grantee: Fernando de Queiroz Cunha
• Support Opportunities: Research Grants - Research, Innovation and Dissemination Centers - RIDC
• FAPESP's process: 21/08847-9 - Contribution of autophagic processes in perivascular adipose tissue hyperinflammation associated with metabolic syndrome
• Grantee: Rafael Menezes da Costa
• Support Opportunities: Scholarships in Brazil - Post-Doctoral