Cilostazol Protects Endothelial Cells Against Lipopolysaccharide-Induced Apoptosis Through ERK1/2- and P38 MAPK-Dependent Pathways.
10.3904/kjim.2009.24.2.113
- Author:
Jong Hoon LIM
1
;
Jae Suk WOO
;
Yung Woo SHIN
Author Information
1. Department of Internal Medicine, Pusan National University College of Medicine, Busan, Korea.
- Publication Type:Original Article
- Keywords:
Cilostazol;
Protection, Endothelial Cells;
Apoptosis;
Extracellular signal-Regulated MAP Kinases 1/2;
p38 Mitogen-Activated Protein Kinase
- MeSH:
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
- From:The Korean Journal of Internal Medicine
2009;24(2):113-122
- CountryRepublic of Korea
- Language:English
-
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.
