Contribution Of The NADPH Oxidase Pathway In Vascular Dysfunction Induced By Chikungunya

Contribution Of The NADPH Oxidase Pathway In Vascular Dysfunction Induced By Chikungunya

• Autor
• José Teles de Oliveira Neto
• Co-autores
• Emiliana Pereira Abrão , Juliano de Paula Souza , Josiane Fernandes da Silva , Daniel Rodrigues , Tiago Januário da Costa , Rafael Menezes da Costa , Eurico de Arruda Neto , Rita C Tostes
• Resumo

• Chikungunya virus (CHIKV) is associated with bradycardia, hypotension, and other cardiovascular disorders. The redox balance is essential to maintain cardiovascular homeostasis. However, if the CHIKV infection induces oxidative stress, leading to vascular dysfunction is still unclear. To test this association, mice and endothelial cells were infected with CHIKV and evaluated. Six-weeks male C57BL/6J mice were divided into two experimental groups: 1) Infected with CHIKV for 48 h; 2) Mock vehicle; infused via intra-caudal with CHIKV (1.0x10⁶ PFU) or culture medium. Vascular function was assessed in aortic rings using a myograph to record isometric tension. Endothelial cells (EA.hy926) were infected with CHIKV with MOI 1.0. ROS production was evaluated by lucigenin chemiluminescence and protein expression by western blot. The statistical difference was considered when p<0.05.  Ethics Committee on Animal Experimentation at Ribeirao Preto Medical School (171/2019). The infected mice showed a reduced vasoconstrictor response to Phe (Emax CHIKV = 126,8±4,340*; Emax Mock = 178,8±5,042), which was restored by NOS inhibitor (L-NAME 300uM) (Emax CHIKV = 219,7±10,66; Emax Mock= 214,4±6,809) and after removing the endothelium. There was no difference in vasorelaxation response to Ach (Emax CHIKV = 88,22±2,846); Emax Mock= 85,37±1,782). CHIKV increased ROS generation in the aortas of mice [Lucigenin (RLU) – Basal: 88.6±4.7; CHIKV: 163.7±17.0]. CHIKV infection increased NOX 4, p22phox aortic protein. CHIKV also upregulated adhesion molecule (ICAM) and marker of the apoptotic pathway activation CHIKV (p21). Moreover, CHIKV induced ROS production and increased NOX4, p21, and ICAM endothelial protein expression. GKT137831 (NOX1/4 inhibitor) attenuated p21 endothelial expression, but not ICAM expression. These data suggest that CHIKV-induced NOX1/4-dependent ROS production an NOS signaling disturbance leads to vascular dysfunction and endothelial cell activation. Moreover, these results provide new evidence for the involvement of oxidative stress in the pathogenesis of Chikungunya. 

  Financial Support: FAPESP, CAPES, CNPq.

• Palavras-chave
• Chikungunya virus, Vascular Reactivity, Reactive Oxygen Species
• Modalidade
• Comunicação oral
• Área Temática
• Estresse oxidativo