Acute Chikungunya Infection Induces Vascular Dysfunction by Directly Disrupting Redox Signaling in Endothelial Cells

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de Oliveira-Neto, Jose Teles ; Souza, Juliano de P. ; Rodrigues, Daniel ; Machado, Mirele R. ; Alves, Juliano V. ; Barros, Paula R. ; Bressan, Alecsander F. ; Silva, Josiane F. ; Costa, Tiago J. ; Costa, Rafael M. ; Bonaventura, Daniella ; Arruda-Neto, Eurico de ; Tostes, Rita C. ; Abrao, Emiliana P.

• Tipo de documento: Artigo Científico
• Fonte: CELLS; v. 13, n. 21, p. 18-pg., 2024-11-01.

Resumo

Chikungunya virus (CHIKV) infection is characterized by febrile illness, severe joint pain, myalgia, and cardiovascular complications. Given that CHIKV stimulates reactive oxygen species (ROS) and pro- and anti-inflammatory cytokines, events that disrupt vascular homeostasis, we hypothesized that CHIKV induces arterial dysfunction by directly impacting redox-related mechanisms in vascular cells. Wild-type (WT) and iNOS knockout (iNOS-/-) mice were administered either CHIKV (1.0 x 106 PFU/mu L) or Mock vehicle via the intracaudal route. In vivo, CHIKV infection induced vascular dysfunction (assessed by a wire myograph), decreased systolic blood pressure (tail-cuff plethysmography), increased IL-6 and IFN-gamma, but not TNF-alpha levels (determined by ELISA), and increased protein content by Western blot. Marked contractile hyporesponsiveness to phenylephrine was observed 48 h post-infection, which was restored by endothelium removal. L-NAME, 1400W, Tiron, and iNOS gene deletion prevented phenylephrine hyporesponsiveness. CHIKV infection increased vascular nitrite concentration (Griess reaction) and superoxide anion (O2 center dot-) generation (lucigenin chemiluminescence), and decreased hydrogen peroxide (H2O2, by Amplex Red) levels 48 h post-infection, alongside increased TBARS levels. In vitro, CHIKV infected endothelial cells (EA.hy926) and upregulated ICAM-1 and iNOS protein expression (determined by Western blot). These data support the conclusion that CHIKV-induced alterations in vascular ROS/NF-kB/iNOS/NO signaling potentially contribute to cardiovascular events associated with Chikungunya infection. (AU)

• Processo FAPESP: 17/08176-1 - Vias de sinalização que influenciam o desenvolvimento de doenças inflamatórias como alvos terapêuticos.
• Beneficiário: Emiliana Pereira Abrão da Costa
• Modalidade de apoio: Bolsas no Brasil - Pós-Doutorado
• Processo FAPESP: 13/08216-2 - CPDI - Centro de Pesquisa em Doenças Inflamatórias
• Beneficiário: Fernando de Queiroz Cunha
• Modalidade de apoio: Auxílio à Pesquisa - Centros de Pesquisa, Inovação e Difusão - CEPIDs