Upregulation of Dickkopf1 by oscillatory shear stress accelerates atherogenesis
Upregulation of Dickkopf1 by oscillatory shear stress accelerates atherogenesis
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振荡剪切应力上调 Dickkopf1 可加速动脉粥样硬化形成
DOI：
10.1007/s00109-015-1369-9
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发表时间：
2016-04-01
影响因子：
4.7
通讯作者：
Zhang, Mei
中科院分区：
文献类型：
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作者：
Li, Mengmeng;Liu, Xinxin;Zhang, Mei
Dickkopf（DKK）1在动脉粥样硬化中的作用已被大量临床研究所证实，但其作用机制尚不清楚。本研究旨在探讨在振荡剪切应力下DKK 1在动脉粥样硬化发展中的作用。振荡剪切力作用于内皮细胞可诱导DKK 1表达，其表达在6 h达到峰值。通过慢病毒基因递送的siRNA敲低或沉默DKK 1抵消了振荡剪切应力诱导的单核细胞粘附增加和内皮紧密连接受损，从而减轻了ApoE−/−小鼠的动脉粥样硬化形成。此外，内皮蛋白酶激活受体1（PAR 1）及其下游转录因子cAMP反应元件结合蛋白（CREB）的激活，是在振荡剪切应力下DKK 1表达增加的关键。我们提供的证据表明，DKK 1有助于动脉粥样硬化的发展条件下的振荡剪切应力。更好地理解DKK 1在动脉粥样硬化形成中的作用可能为临床医生提供预防动脉粥样硬化的机会。关键信息扰动振荡流增加DKK 1表达。DKK 1敲低减弱OSS诱导的单核细胞粘附和内皮损伤。DKK 1的遗传沉默限制ApoE-/-小鼠的动脉粥样硬化形成。PAR 1/PAR 1基因的激活可以抑制内皮细胞的粘附。CREB通路通过OSS上调DKK 1的表达，DKK 1在动脉粥样硬化的治疗中具有重要的应用前景。
AbstractNumerous 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 messageDisturbed 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.