Abstract
Background/aims:
We examined the effects of cilostazol on mitogen-activated protein kinase (MAPK) activity and its relationship with cilostazol-mediated protection against apoptosis in lipopolysaccharide (LPS)-treated endothelial cells.
Methods:
Human umbilical vein endothelial cells (HUVECs) were exposed to LPS and cilostazol with and without specific inhibitors of MAPKs; changes in MAPK activity in association with cell viability and apoptotic signaling were investigated.
Results:
Cilostazol protected HUVECs against LPS-induced apoptosis by suppressing the mitochondrial permeability transition, cytosolic release of cytochrome c, and subsequent activation of caspases, stimulating extracellullar signal-regulated kinase (ERK1/2) and p38 MAPK signaling, and increasing phosphorylated cAMP-responsive element-binding protein (CREB) and Bcl-2 expression, while suppressing Bax expression. These cilostazol-mediated cellular events were effectively blocked by MAPK/ERK kinase (MEK1/2) and p38 MAPK inhibitors.
Conclusions:
Cilostazol protects HUVECs against LPS-induced apoptosis by suppressing mitochondria-dependent apoptotic signaling. Activation of ERK1/2 and p38 MAPKs, and subsequent stimulation of CREB phosphorylation and Bcl-2 expression, may be responsible for the cellular signaling mechanism of cilostazol-mediated protection.
Keywords:
Apoptosis; Cilostazol; Extracellular signal-Regulated MAP Kinases 1/2; Protection, Endothelial Cells; p38 Mitogen-Activated Protein Kinase.
MeSH terms
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Apoptosis / drug effects*
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Caspases / metabolism
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Cell Line
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Cell Survival / drug effects
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Cilostazol
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Cyclic AMP Response Element-Binding Protein / metabolism
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Cytochromes c / metabolism
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Dose-Response Relationship, Drug
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Endothelial Cells / drug effects*
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Endothelial Cells / enzymology
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Endothelial Cells / pathology
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Humans
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Lipopolysaccharides / toxicity*
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Mitochondrial Membrane Transport Proteins / drug effects
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Mitochondrial Membrane Transport Proteins / metabolism
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Mitochondrial Permeability Transition Pore
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Mitogen-Activated Protein Kinase 1 / antagonists & inhibitors
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Mitogen-Activated Protein Kinase 1 / metabolism*
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Mitogen-Activated Protein Kinase 3 / antagonists & inhibitors
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Mitogen-Activated Protein Kinase 3 / metabolism*
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Phosphodiesterase Inhibitors / pharmacology*
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Phosphorylation
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Protein Kinase Inhibitors / pharmacology
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Proto-Oncogene Proteins c-bcl-2 / metabolism
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Signal Transduction / drug effects*
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Tetrazoles / pharmacology*
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Time Factors
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bcl-2-Associated X Protein / metabolism
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p38 Mitogen-Activated Protein Kinases / antagonists & inhibitors
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p38 Mitogen-Activated Protein Kinases / metabolism*
Substances
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BAX protein, human
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CREB1 protein, human
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Cyclic AMP Response Element-Binding Protein
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Lipopolysaccharides
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Mitochondrial Membrane Transport Proteins
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Mitochondrial Permeability Transition Pore
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Phosphodiesterase Inhibitors
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Protein Kinase Inhibitors
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Proto-Oncogene Proteins c-bcl-2
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Tetrazoles
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bcl-2-Associated X Protein
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Cytochromes c
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Mitogen-Activated Protein Kinase 1
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Mitogen-Activated Protein Kinase 3
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p38 Mitogen-Activated Protein Kinases
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Caspases
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Cilostazol