Cytokine storm in individuals with severe COVID-19 decreases endothelial cell antioxidant defense via downregulation of the Nrf2 transcriptional factor

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Rodrigues, Daniel ; Machado, Mirele R. ; Alves, Juliano V. ; Fraga-Silva, Thais F. C. ; Martins, Ronaldo B. ; Campos, Ligia C. B. ; Francisco, Daniely F. ; Couto, Ariel E. S. ; Bonato, Vania L. D. ; Arruda, Eurico ; Becari, Christiane ; Auxiliadora-Martins, Maria ; Louzada-Junior, Paulo ; Costa, Rafael M. ; Tostes, Rita C.

• Document type: Journal article
• Source: AMERICAN JOURNAL OF PHYSIOLOGY-HEART AND CIRCULATORY PHYSIOLOGY; v. 325, n. 2, p. 12-pg., 2023-08-01.

Abstract

The cytokine storm in SARS-CoV-2 infection contributes to the onset of inflammation and target-organ damage. The endothelium is a key player in COVID-19 pathophysiology and it is an important target for cytokines. Considering that cytokines trigger oxidative stress and negatively impact endothelial cell function, we sought to determine whether serum from individuals with severe COVID-19 decreases endothelial cells' main antioxidant defense, i.e., the antioxidant transcriptional factor Nrf2. Human umbilical vein endothelial cells (HUVECs) were incubated with serum from patients with severe COVID-19 at different time points and the effects on redox balance and Nrf2 activity were determined. Serum from individuals with COVID-19 increased oxidant species, as indicated by higher DHE (dihydroethydine) oxidation, increased protein carbonylation, and induced mitochondrial reactive oxygen species (ROS) generation and dysfunction. Serum from patients with COVID-19, but not serum from healthy individuals, induced cell death and diminished nitric oxide (NO) bioavailability. In parallel, Nrf2 nuclear accumulation and the expression of Nrf2-targeted genes were decreased in endothelial cells exposed to serum from individuals with COVID-19. In addition, these cells exhibited higher expression of Bach-1, a negative regulator of Nrf2 that competes for DNA binding. All events were prevented by tocilizumab, an IL-6 receptor blocker, indicating that IL-6 is key to the impairment of endothelial antioxidant defense. In conclusion, endothelial dysfunction related to SARS-CoV-2 infection is linked to decreased endothelial antioxidant defense via IL-6-dependent mechanisms. Pharmacological activation of Nrf2 may decrease endothelial cell damage in individuals with severe COVID-19. (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: 19/11213-1 - Multiusuary equipament in the grant 2017/21629-5, flow cytometry FACS melody 2-lasers, 6-colors (4-2) blue violet
• Grantee: Vânia Luiza Deperon Bonato
• Support Opportunities: Multi-user Equipment Program
• 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
• FAPESP's process: 21/09273-6 - Study of the role of O-glycosylation with N-acetyl-glucosamine (O-GlcNAc) in vascular stress induced by supraphysiological aldosterone concentrations
• Grantee: Daniel Rodrigues
• Support Opportunities: Scholarships in Brazil - Doctorate (Direct)