Upregulation of Dickkopf1 by oscillatory shear stress accelerates atherogenesis - PubMed (original) (raw)

doi: 10.1007/s00109-015-1369-9. Epub 2015 Nov 26.

Xinxin Liu 1, Yu Zhang 1, Mingxue Di 1, Han Wang 1, Lin Wang 1, Yifei Chen 1, Xiaoling Liu 1, Xiaoqing Cao 1, Renya Zeng 1, Yun Zhang 1, Mei Zhang 2 3

Affiliations

Upregulation of Dickkopf1 by oscillatory shear stress accelerates atherogenesis

Mengmeng Li et al. J Mol Med (Berl). 2016 Apr.

Abstract

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.

Key message: 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.

Keywords: Atherosclerosis; DKK1; Endothelial tight junction; Monocyte adhesion; Oscillatory shear stress.

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