Received for publication November 10, 2005.
Revised March 15, 2006.
Accepted for publication March 16, 2006.

Cilostazol Suppresses Superoxide Production and Expression of Adhesion Molecules in Human Endothelial Cells via Mediation of cAMP-dependent Protein Kinase-mediated Maxi-K Channel Activation

Abstract

This study shows whether increased intracellular cAMP level by cilostazol is directly coupled to its maxi-K channel activation in human endothelial cells. Cilostazol (1 µM) increased the K⁺ currents in the human endothelial cells by activating maxi-K channels, which was abolished by iberiotoxin (100 nM), a maxi-K channel blocker. Upon incubation of human coronary artery endothelial cells with TNF- (50 ng/ml), monocyte adhesion significantly increased with increased superoxide generation and expression of VCAM-1 and MCP-1 accompanied by increased degradation of IB in cytoplasm, and activation of NF-B p65 in nucleus. All these variables were significantly suppressed by cilostazol (10 µM), which were antagonized by iberiotoxin (1 µM) as well as by KT5720 (300 nM, cAMP-dependent protein kinase inhibitor), but not by KT5823 (300 nM, cGMP-dependent protein kinase inhibitor). In the human endothelial cells transfected with siRNA targeting maxi-K channels, cilostazol did not suppress the superoxide generation, VCAM-1 and MCP-1 expressions, and monocyte adhesion as contrasted to the wild type cells. These findings were similarly evident with BMS 204352, a maxi-K channel opener, and forskolin and dibutyryl cAMP. In conclusion, increased cAMP level by cilostazol is directly coupled to its maxi-K channel opening action via protein kinase activation in human endothelial cells, thereby suppressing TNF--stimulated superoxide production and expression of adhesion molecules.

Key words: Cilostazol, Human Endothelial Cells, MCP-1, Maxi-K channel, Superoxide, VCAM-1

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