Journal
RHEUMATOLOGY
Volume 54, Issue 6, Pages 1093-1102Publisher
OXFORD UNIV PRESS
DOI: 10.1093/rheumatology/keu421
Keywords
rheumatoid arthritis; sonic hedgehog signalling pathway; smoothened protein; apoptosis; endothelial cells
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Funding
- National Natural Science Foundation of China [81072480]
- Natural Science Foundation of Guangdong Province, China [10151008901000210, S2012020010927]
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Objective. The aim of this study was to investigate the expression of smoothened protein (Smo), a sonic hedgehog (Shh) signalling component, in synovium of RA and its role in the survival and apoptosis of endothelial cells. Methods. The expression of Smo pxrotein in RA synovial tissue was examined by immunohistochemistry. Real-time PCR and western blotting techniques were employed to measure the expression of Shh signalling components in EA.hy926 endothelial cells exposed to TNF-alpha in the presence or absence of cyclopamine (a Smo-specific antagonist). Lastly, the effect of cyclopamine and Smo small interfering RNA on apoptosis induced by TNF-alpha and actinomycin D (ActD) was determined. Results. We found that Smo was highly expressed in synovial tissues of RA, especially in endothelial cells, compared with the trauma group. TNF-alpha significantly increased the expression of Shh signalling components in EA.hy926 endothelial cells, while cyclopamine decreased the expression of Shh signalling components. EA.hy926 endothelial cells treated with various concentrations of cyclopamine (2-8 mu mol/l) showed a significant decrease in cell viability and cell survival rate, and an increase in the rate of cell apoptosis compared with endothelial cells treated with TNF-alpha and ActD (P < 0.05). EA.hy926 endothelial cells transfected with Smo-siRNA also showed a lower cell survival rate and higher apoptotic rate, compared with cells in the control group (P < 0.05). Conclusion. The Shh signalling pathway plays a role in regulating endothelial cell apoptosis in a Smo-dependent manner.
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