Atheroprotective Effect of Laminar Fluid Shear Stress in Endothelial Cells: Possible Role of Mitogen-Activated Protein Kinases

DOI Web Site PubMed 被引用文献7件 参考文献43件
  • Yoshizumi Masanori
    Department of Pharmacology, The University of Tokushima School of Medicine
  • Abe Jun-ichi
    Center for Cardiovascular Research, University of Rochester School of Medicine and Dentistry
  • Tsuchiya Koichiro
    Department of Pharmacology, The University of Tokushima School of Medicine
  • Berk Bradford C.
    Center for Cardiovascular Research, University of Rochester School of Medicine and Dentistry
  • Tamaki Toshiaki
    Department of Pharmacology, The University of Tokushima School of Medicine

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  • Stress and Vascular Responses: Atheroprotective Effect of Laminar Fluid Shear Stress in Endothelial Cells: Possible Role of Mitogen-Activated Protein Kinases

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Atherosclerosis preferentially occurs in areas of turbulent blood flow and low fluid shear stress, whereas laminar blood flow and high shear stress are atheroprotective. Inflammatory cytokines, such as tumor necrosis factor-α (TNF-α), stimulate expression of endothelial cell (EC) genes that may promote atherosclerosis. Recent findings suggest a steady laminar blood flow decreases EC apoptosis and inhibits TNF-mediated EC activation. EC apoptosis or activation is suggested to be involved in plaque erosion, which may lead to platelet aggregation. TNF-α regulates gene expression in ECs, in part, by stimulating mitogen-activated protein (MAP) kinases, which phosphorylate transcription factors. We hypothesized that steady laminar flow inhibits cytokine-mediated activation of MAP kinases in ECs. To test this hypothesis, we determined the effects of steady laminar flow (shear stress = 12 dynes/cm2) on TNF-α-stimulated activity of three MAP kinases in human umbilical vein ECs (HUVEC): extracellular signal-regulated kinase (ERK1/2), c-Jun N-terminal kinase (JNK), and p38. TNF-α activated ERK1/2, JNK, and p38 maximally at 15 min in HUVEC. Pre-exposing HUVEC for 10 min to flow inhibited TNF-α activation of JNK, but showed no significant effect on ERK1/2 or p38 activation. Incubation of HUVEC with PD98059, a specific ERK1/2 inhibitor, blocked the flow-mediated inhibition of TNF activation of JNK. Transfection studies with dominant-negative constructs of the protein kinase MEK5 suggested an important role for big mitogen-activated protein kinase 1 (BMK1) in flow-mediated regulation of EC activation by TNF-α. Understanding the mechanisms by which steady laminar flow regulates JNK activation by cytokines may provide insight into the atheroprotective mechanisms induced by laminar blood flow.<br>

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