Abstract
Objective:
Angiotensin-II (Ang-II) promotes the interaction of mononuclear cells with arterioles and neutrophils with postcapillary venules. To investigate the mechanisms underlying this dissimilar response, the involvement of fractalkine (CX(3)CL1) was explored.
Methods and results:
Enhanced CX(3)CL1 expression was detected in both cremasteric arterioles and postcapillary venules 24 hours after Ang-II intrascrotal injection. Arteriolar leukocyte adhesion was the unique parameter significantly reduced (83%) in animals lacking CX(3)CL1 receptor (CX(3)CR1). Human umbilical arterial and venous endothelial cell stimulation with 1 μmol/L Ang-II increased CX(3)CL1 expression, yet neutralization of CX(3)CL1 activity only significantly inhibited Ang-II-induced mononuclear cell-human umbilical arterial endothelial cell interactions (73%) but not with human umbilical venous endothelial cells. The use of small interfering RNA revealed the involvement of tumor necrosis factor-α in Ang-II-induced CX(3)CL1 upregulation and mononuclear cell arrest. Nox5 knockdown with small interfering RNA or pharmacological inhibition of extracellular signal-regulated kinases1/2, p38 mitogen-activated protein kinase, and nuclear factor-κB also abolished these responses. Finally, when human umbilical arterial endothelial cells were costimulated with Ang-II, tumor necrosis factor-α, and interferon-γ, CX(3)CL1 expression and mononuclear cell adhesiveness were more pronounced than when each stimulus was provided alone.
Conclusions:
These results suggest that Ang-II induces functional CX(3)CL1 expression in arterial but not in venous endothelia. Thus, targeting endothelial CX(3)CL1-mononuclear leukocyte CX(3)CR1 interactions may constitute a new therapeutic strategy in the treatment of Ang-II-associated cardiovascular diseases.
Publication types
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Comparative Study
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Research Support, Non-U.S. Gov't
MeSH terms
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Angiotensin II / metabolism*
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Angiotensin II Type 1 Receptor Blockers / pharmacology
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Animals
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Apolipoproteins E / genetics
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Apolipoproteins E / metabolism
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Arteries / drug effects
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Arteries / metabolism*
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Arterioles / drug effects
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Arterioles / metabolism
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Atherosclerosis / genetics
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Atherosclerosis / metabolism
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Atherosclerosis / pathology
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Atherosclerosis / prevention & control
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CX3C Chemokine Receptor 1
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Cell Adhesion
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Cells, Cultured
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Chemokine CX3CL1 / genetics
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Chemokine CX3CL1 / metabolism*
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Disease Models, Animal
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Endothelial Cells / drug effects
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Endothelial Cells / metabolism*
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Extracellular Signal-Regulated MAP Kinases / metabolism
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Female
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Human Umbilical Vein Endothelial Cells / metabolism
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Humans
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Interferon-gamma / metabolism
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Leukocyte Rolling
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Leukocytes / metabolism
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Losartan / pharmacology
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Male
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Membrane Glycoproteins / genetics
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Membrane Glycoproteins / metabolism
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Membrane Proteins / genetics
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Membrane Proteins / metabolism
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Mice
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Mice, Inbred C57BL
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Mice, Knockout
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NADPH Oxidase 2
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NADPH Oxidase 4
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NADPH Oxidase 5
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NADPH Oxidases / genetics
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NADPH Oxidases / metabolism
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NF-kappa B / metabolism
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RNA Interference
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Receptors, Chemokine / genetics
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Receptors, Chemokine / metabolism
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Signal Transduction
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Time Factors
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Transfection
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Tumor Necrosis Factor-alpha / genetics
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Tumor Necrosis Factor-alpha / metabolism
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Veins / drug effects
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Veins / metabolism*
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Venules / drug effects
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Venules / metabolism
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p38 Mitogen-Activated Protein Kinases / metabolism
Substances
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Angiotensin II Type 1 Receptor Blockers
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Apolipoproteins E
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CX3C Chemokine Receptor 1
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CX3CL1 protein, human
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CX3CR1 protein, human
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Chemokine CX3CL1
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Cx3cl1 protein, mouse
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Cx3cr1 protein, mouse
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Membrane Glycoproteins
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Membrane Proteins
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NF-kappa B
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Receptors, Chemokine
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Tumor Necrosis Factor-alpha
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Angiotensin II
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Interferon-gamma
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CYBB protein, human
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NADPH Oxidase 2
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NADPH Oxidase 4
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NADPH Oxidase 5
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NADPH Oxidases
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NOX4 protein, human
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NOX5 protein, human
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Extracellular Signal-Regulated MAP Kinases
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p38 Mitogen-Activated Protein Kinases
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Losartan