Korean J Intern Med.  2009 Jun;24(2):113-122. 10.3904/kjim.2009.24.2.113.

Cilostazol Protects Endothelial Cells Against Lipopolysaccharide-Induced Apoptosis Through ERK1/2- and P38 MAPK-Dependent Pathways

Affiliations
  • 1Department of Internal Medicine, Pusan National University College of Medicine, Busan, Korea.
  • 2Department of Physiology, Pusan National University College of Medicine, Busan, Korea. jswoo@pusan.ac.kr

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 cAMPresponsive 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 mitochondriadependent 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 cilostazolmediated protection.

Keyword

Cilostazol; Protection, Endothelial Cells; Apoptosis; Extracellular signal-Regulated MAP Kinases 1/2; p38 Mitogen-Activated Protein Kinase

MeSH Terms

Apoptosis/*drug effects
Caspases/metabolism
Cell Line
Cell Survival/drug effects
Cyclic AMP Response Element-Binding Protein/metabolism
Cytochromes c/metabolism
Dose-Response Relationship, Drug
Endothelial Cells/*drug effects/enzymology/pathology
Humans
Lipopolysaccharides/*toxicity
Mitochondrial Membrane Transport Proteins/drug effects/metabolism
Mitogen-Activated Protein Kinase 1/antagonists & inhibitors/*metabolism
Mitogen-Activated Protein Kinase 3/antagonists & inhibitors/*metabolism
Phosphodiesterase Inhibitors/*pharmacology
Phosphorylation
Protein Kinase Inhibitors/pharmacology
Proto-Oncogene Proteins c-bcl-2/metabolism
Signal Transduction/*drug effects
Tetrazoles/*pharmacology
Time Factors
bcl-2-Associated X Protein/metabolism
p38 Mitogen-Activated Protein Kinases/antagonists & inhibitors/*metabolism
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