title: Differential regulation of urokinase-type plasminogen activator expression by fluid shear stress in human coronary artery endothelial cells.
abstract: Atherosclerotic plaques preferentially localize at arterial regions exposed to turbulent low-shear flow. Urokinase-type plasminogen activator (uPA) plays a role in vascular remodeling by facilitating smooth muscle cell migration and proliferation in addition to the proteolysis of extracellular matrix, and the expression of uPA is elevated in atherosclerotic lesions. In this study, we analyzed the effects of laminar and turbulent shear stress on uPA expression in cultured human coronary artery endothelial cells. The application of laminar shear stress (1.5 or 15 dyn/cm2) significantly decreased the amount of uPA mRNA as well as the secretion of uPA protein. In contrast, turbulent shear stress (average intensity, 1.5 dyn/cm2) markedly increased uPA gene expression and protein secretion. Laminar shear stress downregulated uPA gene expression transcriptionally and posttranscriptionally; laminar shear stress activated transcription factor GATA6, which binds to a GATA consensus element located between -692 and -687 bp in the uPA promoter, thereby inhibiting uPA gene transcription. Laminar shear stress also accelerated the degradation of uPA mRNA; the half-life of uPA mRNA decreased to about half of the static control's half-life. Although turbulent shear stress had no effect on the transcription of uPA, it significantly increased uPA mRNA stability; the half-life of uPA mRNA increased by about two times the static control's half-life. Our results suggest that endothelial uPA expression is flow sensitive and differentially regulated by laminar and turbulent shear stress in vitro. We speculate that this effect may contribute to the local nature of atherosclerosis.
authors.affiliation: Dept. of Biomedical Engineering, Graduate School of Medicine, Univ. of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan.
authors.forename: Takaaki
authors.initials: T
authors.lastname: Sokabe
authors.forename: Kimiko
authors.initials: K
authors.lastname: Yamamoto
authors.forename: Norihiko
authors.initials: N
authors.lastname: Ohura
authors.forename: Hideki
authors.initials: H
authors.lastname: Nakatsuka
authors.forename: Kairong
authors.initials: K
authors.lastname: Qin
authors.forename: Syotaro
authors.initials: S
authors.lastname: Obi
authors.forename: Akira
authors.initials: A
authors.lastname: Kamiya
authors.forename: Joji
authors.initials: J
authors.lastname: Ando
mesh_terms: D001158:Arteries / Q000378:metabolism; D002478:Cells, Cultured; D003331:Coronary Vessels / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000378:metabolism; D015536:Down-Regulation; D042783:Endothelial Cells / Q000378:metabolism*; D050993:GATA6 Transcription Factor; D015870:Gene Expression / Q000502:physiology; D006207:Half-Life; D006801:Humans; D010960:Plasminogen Activators / Q000235:genetics / Q000378:metabolism*; D020871:RNA Stability; D012333:RNA, Messenger / Q000378:metabolism; D013314:Stress, Mechanical; D014157:Transcription Factors / Q000378:metabolism; D014568:Urokinase-Type Plasminogen Activator / Q000235:genetics / Q000378:metabolism*
chemical_list: D004268:DNA-Binding Proteins; D050993:GATA6 Transcription Factor; C494759:GATA6 protein, human; D012333:RNA, Messenger; D014157:Transcription Factors; D010960:Plasminogen Activators; D014568:Urokinase-Type Plasminogen Activator