期刊
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
卷 98, 期 11, 页码 6476-6481出版社
NATL ACAD SCIENCES
DOI: 10.1073/pnas.101134098
关键词
endothelium; protein kinase; signal transduction
资金
- NHLBI NIH HHS [P01-HL18645, P01 HL018645, R01 HL064839] Funding Source: Medline
- NIGMS NIH HHS [T32 GM007356, T32 GM07356] Funding Source: Medline
Atherosclerosis preferentially occurs in areas of turbulent flow and low fluid shear stress, whereas laminar flow and high shear stress are atheroprotective, Inflammatory cytokines, such as tumor necrosis factor-alpha (TNF-alpha) and IL-1 stimulate expression of endothelial cell (EC) genes that may promote atherosclerosis. TNF-alpha and IL-1 regulate gene expression in ECs, in part, by stimulating mitogen-activated protein kinases (MAPK), which phosphorylate transcription factors. We hypothesized that steady laminar flow inhibits cytokine-mediated activation of MAPK in EC. To test this hypothesis, we determined the effects of flow (shear stress = 12 dynes/cm(2)) on TNF-alpha and IL-1-stimulated activity of three MAPK in human umbilical vein ECs (HUVEC): extracellular signal-regulated kinase (ERK1/2), p38, and c-Jun N-terminal kinase (JNK). Flow alone stimulated ERK1/2 and p38 activity but decreased JNK activity compared with static controls. TNF-alpha or IL-1 alone activated ERK1/2, p38, and JNK maximally at 15 min in HUVEC. Preexposing HUVEC for 10 min to flow inhibited TNF-alpha and IL-1 activation of JNK by 46% and 49%, respectively, but had no significant effect on ERK1/2 or p38 activation. Incubation of HUVEC with PD98059, which inhibits flow-mediated ERK1/2 activation, prevented flow from inhibiting cytokine activation of JNK. Phorbol 12-myristate 13-acetate, which strongly activates ERK1/2, also inhibited TNF-alpha activation of JNK. These findings indicate that fluid shear stress inhibits TNF-alpha -mediated signaling events in HUVEC via the activation of the ERK1/2 signaling pathway. Inhibition of TNF-alpha signal transduction represents a mechanism by which steady laminar flow may exert atheroprotective effects on the endothelium.
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