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
Rok vydání: 2015
Předmět:
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