RESUMO
Atherosclerotic plaques are found in regions exposed to disturbed flow, suggesting the active participation of the hemodynamic environment in atherogenesis. Indeed, unidirectional and oscillatory flow patterns (ie, bidirectional) have been shown to induce contrasting effects on endothelial function. The purpose of the present study was to evaluate the effect of these 2 flow patterns characterizing plaque-free and plaque-prone regions, respectively, on the oxidative stress of endothelial cells. NADH-dependent oxidase activity was shown to be equally induced (2- to 3-fold) in endothelial cells exposed to pulsatile unidirectional or oscillatory flow patterns. Under these flow conditions, an increase in endothelial cell oxidative state compared with static cultures was observed. Pulsatility of flow, but not cyclic stretch, was a critical determinant of flow-induced superoxide anion production. P22phox mRNA level increased in cells exposed to both unidirectional and oscillatory shear stress, suggesting that p22phox gene expression upregulation contributes to flow-induced increase in superoxide anion production in endothelial cells. In conclusion, we demonstrate a flow-induced increase in oxidative stress in endothelial cells. This chronic increase is dependent on the pulsatile nature of flow and is mediated in part by upregulation of an NADH-dependent oxidase expression.
Assuntos
Endotélio Vascular/fisiologia , Proteínas de Membrana Transportadoras , Estresse Oxidativo , Acetilcisteína/farmacologia , Animais , Antioxidantes/farmacologia , Arteriosclerose/metabolismo , Bovinos , Células Cultivadas , Endotélio Vascular/efeitos dos fármacos , Heme Oxigenase (Desciclizante)/metabolismo , Heme Oxigenase-1 , NADPH Desidrogenase/biossíntese , NADPH Desidrogenase/genética , NADPH Oxidases , Óxido Nítrico Sintase/biossíntese , Óxido Nítrico Sintase/genética , Óxido Nítrico Sintase Tipo III , Oxirredução , Fosfoproteínas/biossíntese , Fosfoproteínas/genética , RNA Mensageiro/biossíntese , Estresse Mecânico , Superóxidos/metabolismo , Regulação para Cima/efeitos dos fármacosRESUMO
MAGE genes encode tumor-specific shared antigens that are among the most interesting candidates for cancer vaccines. Despite extensive studies, however, CD8+ T-cell responses to MAGE-derived epitopes have been detected only occasionally in cancer patients, even after vaccination. In contrast with these findings, we report here that HLA-A2 melanoma patients respond frequently to the recently identified peptide MAGE-A10(254-262). Indeed, as assessed by staining with fluorescent HLA-A2/peptide MAGE-A10(254-262) tetramers, CD8+ T cells directed against this peptide were readily detectable in a large proportion of HLA-A2+ melanoma patients. These results provide new insight into the immunogenicity of MAGE antigens and underline the potential usefulness of MAGE-A10 peptide-based cancer vaccines.
