Fluid shear stress inhibits vascular inflammation by decreasing thioredoxin-interacting protein in endothelial cells
AUTOR(ES)
Yamawaki, Hideyuki
FONTE
American Society for Clinical Investigation
RESUMO
Regions in the vasculature that are exposed to steady laminar blood flow are protected from atherosclerosis as compared with regions where flow is disturbed. We found that flow decreased TNF-mediated VCAM1 expression by inhibiting JNK and p38. JNK inhibition correlated with inhibition of apoptosis signal–regulating kinase 1 (ASK1), a JNK and p38 activator. Thioredoxin-interacting protein (TXNIP) is a stress-responsive protein that inhibits thioredoxin (TRX) activity. Since thioredoxin inhibits ASK1, we hypothesized that changes in TXNIP-TRX-ASK1 interactions mediate the antiinflammatory effects of flow. To explore this, we used perfused vessels and cultured ECs. Exposure of rabbit aortae or ECs to normal flow (12 dyn/cm2, 24 hours) was associated with decreased TXNIP expression and increased TRX activity compared with exposure to low flow (0.4 dyn/cm2). Normal flow inhibited TNF activation of JNK/p38 and VCAM1 expression. In cultured ECs, reduction of TXNIP expression by small interfering RNA increased TRX binding to ASK1 and inhibited TNF activation of JNK/p38 and VCAM1 expression. Conversely, overexpression of TXNIP stimulated JNK and p38. In aortae from TXNIP-deficient mice, TNF-induced VCAM1 expression was inhibited. The data suggest that TXNIP and TRX are key components of biomechanical signal transduction and establish them as potentially novel regulators of TNF signaling and inflammation in ECs.
ACESSO AO ARTIGO
http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=546457Documentos Relacionados
- Diabetes induces and calcium channel blockers prevent cardiac expression of proapoptotic thioredoxin-interacting protein
- Transcription Factors Krüppel-Like Factor 6 and Peroxisome Proliferator-Activated Receptor-γ Mediate High Glucose-Induced Thioredoxin-Interacting Protein
- Turbulent fluid shear stress induces vascular endothelial cell turnover in vitro.
- Activation of integrins in endothelial cells by fluid shear stress mediates Rho-dependent cytoskeletal alignment
- Biologically active fragment of a human tRNA synthetase inhibits fluid shear stress-activated responses of endothelial cells