The Phosphodiesterase III Inhibitor Cilostazol Ameliorates Ethanolinduced Endothelial Dysfunction

Author(s): Toshinori Takagi, Keisuke Mishiro, Masamitsu Shimazawa, Shinichi Yoshimura, Toru Iwama, Hideaki Hara

Journal Name: Current Neurovascular Research

Volume 11 , Issue 4 , 2014

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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.

Keywords: Cilostazol, endothelial cell, ethanol, matrix metalloproteinase, phosphodiesterase III inhibitor, reactive oxygen species, tight junction.

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Article Details

Year: 2014
Published on: 16 October, 2014
Page: [302 - 311]
Pages: 10
DOI: 10.2174/1567202611666140912113152
Price: $65

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