Upregulation of Dickkopf1 by oscillatory shear stress accelerates atherogenesis
| Autor: | Han Wang, Xinxin Liu, Yu Zhang, Renya Zeng, Yun Zhang, Mengmeng Li, Mei Zhang, Mingxue Di, Yifei Chen, Lin Wang, Xiaoling Liu, Xiaoqing Cao |
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| Rok vydání: | 2015 |
| Předmět: |
musculoskeletal diseases
0301 basic medicine Transcriptional Activation 030204 cardiovascular system & hematology CREB Mechanotransduction Cellular Monocytes Cell Line 03 medical and health sciences Mice 0302 clinical medicine Downregulation and upregulation Transduction Genetic Drug Discovery Cell Adhesion Gene silencing Animals Humans Receptor PAR-1 Gene Silencing Cell adhesion Cyclic AMP Response Element-Binding Protein Transcription factor Genetics (clinical) Regulation of gene expression Mice Knockout biology Tight junction Chemistry Endothelial Cells Atherosclerosis Cell biology Up-Regulation Disease Models Animal 030104 developmental biology DKK1 Gene Expression Regulation biology.protein Molecular Medicine Intercellular Signaling Peptides and Proteins Stress Mechanical |
| Zdroj: | Journal of molecular medicine (Berlin, Germany). 94(4) |
| ISSN: | 1432-1440 |
| Popis: | Numerous clinical studies have highlighted the pivotal role Dickkopf (DKK) 1 plays in atherosclerosis, but the underlying mechanisms remain unknown. The present study was designed to explore the contribution of DKK1 to the development of atherosclerosis under oscillatory shear stress. Oscillatory shear stress applied to endothelial cells induced DKK1 expression, which peaked at 6 h. siRNA knockdown or silencing DKK1 by lentiviral gene delivery counteracted the increased monocyte adhesion and impaired endothelial tight junction induced by oscillatory shear stress, thereby attenuating atherogenesis in ApoE-/- mice. As well, activation of endothelial proteinase-activated receptor 1 (PAR1) and its downstream transcription factor, cAMP response element-binding protein (CREB), was critical to the increased expression of DKK1 under oscillatory shear stress. We provide evidence that DKK1 contributes to the development of atherosclerosis under conditions of oscillatory shear stress. A better understanding of the role played by DKK1 in atherogenesis may provide clinicians with opportunities to prevent atherosclerosis.Disturbed oscillatory flow increases DKK1 expression. DKK1 knockdown attenuates OSS-induced monocyte adhesion and endothelial impairment. Genetic silencing of DKK1 limits atherogenesis in ApoE-/- mice. Activation of the PAR1/CREB pathway contributes to the upregulation of DKK1 via OSS. DKK1 is a promising candidate with respect to the treatment of atherosclerosis. |
| Databáze: | OpenAIRE |
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