The Phosphodiesterase III Inhibitor Cilostazol Ameliorates Ethanolinduced Endothelial Dysfunction
2014
Intracranial hemorrhage (ICH) remains a devastating disease, and heavy alcohol consumption is an underlying
risk factor. The aim of this study was to study the mechanism of ethanol-induced endothelial cell damage and to evaluate
the protective effect of cilostazol against ethanol-induced damage. We first evaluated transendothelial electrical resistance
(TEER) and cell viability of human brain microvascular endothelial cells at the ethanol concentration shown to cause
mild-to-moderate intoxication in the clinic. We also assessed the permeability of fluorescein isothiocyanate (FITC)-
dextran and the change in tight junction proteins. Furthermore, we studied the potential of cilostazol to protect endothelial
cells from ethanol-induced dysfunction. Concentration- and time-dependent effects of ethanol on cell viability and TEER
showed that TEER was reduced at each concentration of ethanol tested during exposures of >2 h, but cell viability was not
changed. Permeability of FITC-dextran was enhanced, and both tight junction and adherens junction proteins were
reduced by 3-h ethanol treatment. The permeability of FITC-dextran was ameliorated by administration of cilostazol in a
concentration-dependent manner. The protective effect of cilostazol was obstructed by administration of a protein kinase
A inhibitor. Using gelatin zymography, we found that the protective effect of cilostazol was by reducing matrix
metalloproteinase 9 (MMP-9) activation, but it had no effect on reactive oxygen spices (ROS). Our results indicate that
cilostazol protected endothelial cells against ethanol-induced endothelial dysfunction by inhibiting ROS-mediated
activation of MMP-9.
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