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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概要
- 論文の詳細を見る
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.
- 社団法人 日本薬理学会の論文
- 2003-03-01
著者
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吉栖 正典
奈良県立医科大学 薬理学講座
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Tamaki Toshiaki
Department of Pharmacology, IHBS, the University of TOKUSHIMA Graduate school
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Yoshizumi Masanori
Department of Pharmacology, Nara Medical University
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TSUCHIYA Koichiro
Department of Pharmacology, The University of Tokushima Graduate School of Medical Sciences
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ABE Jun-ichi
Center for Cardiovascular Research, University of Rochester School of Medicine and Dentistry
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BERK Bradford
Center for Cardiovascular Research, University of Rochester School of Medicine
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Tamaki T
Department Of Pharmacology The Institute Of Health Bioscience The University Of Tokushima Graduate S
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Abe Jun-ichi
Center For Cardiovascular Research University Of Rochester School Of Medicine And Dentistry
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Berk Bradford
Center For Cardiovascular Research University Of Rochester School Of Medicine
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Berk Bradford
Center For Cardiovascular Research University Of Rochester
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Tamaki Toshiaki
The Department Of Pharmacology Kagawa Medical School
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Tamaki Toshiaki
Department Of Pharmacology Kagawa Medical School
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Tsuchiya Koichiro
Department Of Clinical Pharmacology Institute Of Health Biosciences The University Of Tokushima Grad
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Yoshizumi Masanori
Dep. Of Pharmacology Nara Medical Univ. School Of Medicine Jpn
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Tamaki T
Department Of Molecular Engineering National Institute Of Materials And Chemical Research
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Yoshizumi Masanori
Department Of Pharmacology Nara Medical University School Of Medicine
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Yosizumi Masanori
Department Of Pharmacology The University Of Tokushima School Of Medicine
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Kitaichi T
Department Of Cardiovascular Surgery The University Of Tokushima Graduate School Of Health Bioscienc
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Takeichi Toshiaki
Department Of Internal Medicine Health Insurance Naruto Hospital
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Tsuchiya Koichiro
Department Of Cardiovascular Surgery The University Of Tokushima Graduate School Of Health Bioscienc
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Berk BC
Center for Cardiovascular Research, University of Rochester School of Medicine
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