Suppression of endothelial t-PA expression by prolonged high laminar shear stress.
Primary hypertension is associated with an impaired capacity for acute release of endothelial tissue-type plasminogen activator (t-PA), which is an important local protective response to prevent thrombus extension. As hypertensive vascular remodeling potentially results in increased vascular wall shear stress, we investigated the impact of shear on regulation of t-PA. Cultured human endothelial cells were exposed to low (< or =1.5 dyn/cm(2)) or high (25 dyn/cm(2)) laminar shear stress for up to 48 h in two different experimental models. Using real-time RT-PCR and ELISA, shear stress was observed to time and magnitude-dependently suppress t-PA transcript and protein secretion to approximately 30% of basal levels. Mechanistic experiments revealed reduced nuclear protein binding to the t-PA specific CRE element (EMSA) and an almost completely abrogated shear response with pharmacologic JNK inhibition. We conclude that prolonged high laminar shear stress suppresses endothelial t-PA expression and may therefore contribute to the enhanced risk of arterial thrombosis in hypertensive disease.
Ulfhammer
Erik
E
Clinical Experimental Research Laboratory, Sahlgrenska University Hospital/Ostra, SE 416 85 Gothenburg, Sweden.
Carlström
Maria
M
Bergh
Niklas
N
Larsson
Pia
P
Karlsson
Lena
L
Jern
Sverker
S
D001483:Base Sequence; D002478:Cells, Cultured; D051699:Cyclic AMP Response Element-Binding Protein A / Q000378:metabolism; D024202:Electrophoretic Mobility Shift Assay; D004730:Endothelium, Vascular / Q000201:enzymology*; D004794:Enzyme Repression; D015870:Gene Expression; D015971:Gene Expression Regulation, Enzymologic; D006801:Humans; D006973:Hypertension / Q000201:enzymology / Q000503:physiopathology; D048670:MAP Kinase Kinase 4 / Q000378:metabolism; D033081:Shear Strength; D013314:Stress, Mechanical; D013927:Thrombosis / Q000201:enzymology / Q000503:physiopathology; D010959:Tissue Plasminogen Activator / Q000096:biosynthesis / Q000235:genetics*
D051699:Cyclic AMP Response Element-Binding Protein A; D048670:MAP Kinase Kinase 4; D010959:Tissue Plasminogen Activator