title: Upregulation of Dickkopf1 by oscillatory shear stress accelerates atherogenesis.
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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: The Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education and Chinese Ministry of Health, Qilu Hospital, Shandong University, Jinan, 250012, China.
authors.forename: Mengmeng
authors.initials: M
authors.lastname: Li
authors.affiliation: The Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education and Chinese Ministry of Health, Qilu Hospital, Shandong University, Jinan, 250012, China.
authors.forename: Xinxin
authors.initials: X
authors.lastname: Liu
authors.affiliation: The Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education and Chinese Ministry of Health, Qilu Hospital, Shandong University, Jinan, 250012, China.
authors.forename: Yu
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: The Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education and Chinese Ministry of Health, Qilu Hospital, Shandong University, Jinan, 250012, China.
authors.forename: Mingxue
authors.initials: M
authors.lastname: Di
authors.affiliation: The Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education and Chinese Ministry of Health, Qilu Hospital, Shandong University, Jinan, 250012, China.
authors.forename: Han
authors.initials: H
authors.lastname: Wang
authors.affiliation: The Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education and Chinese Ministry of Health, Qilu Hospital, Shandong University, Jinan, 250012, China.
authors.forename: Lin
authors.initials: L
authors.lastname: Wang
authors.affiliation: The Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education and Chinese Ministry of Health, Qilu Hospital, Shandong University, Jinan, 250012, China.
authors.forename: Yifei
authors.initials: Y
authors.lastname: Chen
authors.affiliation: The Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education and Chinese Ministry of Health, Qilu Hospital, Shandong University, Jinan, 250012, China.
authors.forename: Xiaoling
authors.initials: X
authors.lastname: Liu
authors.affiliation: The Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education and Chinese Ministry of Health, Qilu Hospital, Shandong University, Jinan, 250012, China.
authors.forename: Xiaoqing
authors.initials: X
authors.lastname: Cao
authors.affiliation: The Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education and Chinese Ministry of Health, Qilu Hospital, Shandong University, Jinan, 250012, China.
authors.forename: Renya
authors.initials: R
authors.lastname: Zeng
authors.affiliation: The Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education and Chinese Ministry of Health, Qilu Hospital, Shandong University, Jinan, 250012, China.
authors.forename: Yun
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: The Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education and Chinese Ministry of Health, Qilu Hospital, Shandong University, Jinan, 250012, China. daixh@vip.sina.com.|Department of Cardiology, Qilu Hospital, Shandong University, 107#, Wen Hua Xi Road, Jinan, Shandong, 250012, People's Republic of China. daixh@vip.sina.com.
authors.forename: Mei
authors.initials: M
authors.lastname: Zhang
mesh_terms: D000818:Animals; D050197:Atherosclerosis / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D002448:Cell Adhesion; D002460:Cell Line; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D004195:Disease Models, Animal; D042783:Endothelial Cells / Q000378:metabolism; D005786:Gene Expression Regulation; D020868:Gene Silencing; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D040542:Mechanotransduction, Cellular; D051379:Mice; D018345:Mice, Knockout; D009000:Monocytes / Q000378:metabolism; D044463:Receptor, PAR-1 / Q000378:metabolism; D013314:Stress, Mechanical; D015533:Transcriptional Activation; D014161:Transduction, Genetic; D015854:Up-Regulation
chemical_list: D017362:Cyclic AMP Response Element-Binding Protein; C501127:Dkk1 protein, mouse; D036341:Intercellular Signaling Peptides and Proteins; D044463:Receptor, PAR-1
keywords: Atherosclerosis; DKK1; Endothelial tight junction; Monocyte adhesion; Oscillatory shear stress