期刊
CARDIOVASCULAR RESEARCH
卷 60, 期 3, 页码 488-496出版社
ELSEVIER SCIENCE BV
DOI: 10.1016/j.cardiores.2003.09.010
关键词
blood flow; endothelial function; signal transduction; gene expression; IKCaI; K-channel
Objective: Wall shear stress associated with blood flow is a major stimuli for generation of endothelial vasodilating and antithrombotic factors and it also regulates endothelial gene expression. Activation of endothelial intermediate-conductance Ca2+-activated K+ channels (IKCa) is important for the control of endothelial function by inducing cell hyperpolarization and thus generation of the endothelium-derived hyperpolarizing factor. In the present study we tested whether the IKCa encoding IKCa1 gene is regulated by laminar shear stress (LSS). Methods: Human umbilical vein endothelial cells (HUVEC) were subjected to LSS with a magnitude of 0.5-15 dyn/cm(2) and time intervals of 2-24 h in a flow cone apparatus. Expression of the IKCa1 gene and IKCa-functions were determined by using real time RT-PCR and patch-clamp techniques. Results: A short 2-4 h-or long 24 h-exposure to a LSS with a low (venous) magnitude of 0.5 dyn/cm(2) had no effect on IKCa1 expression levels. An exposure for 2 and 4 h to LSS with an intermediate magnitude of 5 dyn/cm(2) was also ineffective, whereas an exposure for 24 h induced a significant threefold up-regulation of IKCa1 expression levels. An exposure to LSS with a higher (arterial) magnitude of 15 dyn/cm(2), resulted in an eightfold up-regulation of IKCa1 expression levels after a 4 h-exposure and a fourfold increase of IKCa1 expression levels at 24 h. The increased IKCa1 expression levels following exposure to high levels of LSS resulted in enhanced IKCa whole-cell currents and in an increased hyperpolarization of the endothelium in response to ATP and the IKCa opener 1-EBIO. Inhibition of the mitogen-activated protein kinase/extracellular-signal-regulated kinase (ER-K) kinase 1/2 (MEK/ERK) pathway by PD98059 prevented the LSS-induced up-regulation of IKCa1 expression levels and IKCa whole-cell currents indicating that augmentation of IKCa1 expression levels is mediated by the LSS-induced activation of the MEK/ERK pathway. Conclusion: Long term exposure to LSS up-regulates expression and function of endothelial IKCa. This increase might represent a new important mechanism in endothelial adaptation to altered hemodynamics. (C) 2003 European Society of Cardiology. Published by Elsevier B.V. All rights reserved.
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