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KMID : 0043320080310101291
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Archives of Pharmacal Research
2008 Volume.31 No. 10 p.1291 ~ p.1301
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APE1/Ref-1 Promotes the Effect of Angiotensin II on Ca2+-Activated K+ Channel in Human Endothelial Cells via Suppression of NADPH Oxidase
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Han Jin
Choi Tae-Hoon
Kim Hyoung-Kyu
Sohn Yoon-Kyung
Park Won-Sun
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Abstract
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The effects of angiotensin II (Ang II) on whole-cell large conductance Ca2+-activated K+ (BKCa) currents was investigated in control and Apurinic/apyrimidinic endonuclease1/redox factor 1 (APE1/Ref-1)-overexpressing human umbilical vein endothelial cells (HUVECs). Ang II blocked the BKCa current in a dose-dependent fashion, and this inhibition was greater in APE1/Ref-1-overexpressing HUVECs than in control HUVECs (half-inhibition values of 102.81 ± 9.54 nM and 11.34 ± 0.39 nM in control and APE1/Ref-1-overexpressing HUVECs, respectively). Pretreatment with the NADPH oxidase inhibitor diphenyleneiodonium (DPI) or knock down of NADPH oxidase (p22 phox) using siRNA increased the inhibitory effect of Ang II on the BKCa currents, similar to the effect of APE1/ Ref-1 overexpression. In addition, application of Ang II increased the superoxide and hydrogen peroxide levels in the control HUVECs but not in APE1/Ref-1-overexpressing HUVECs. Furthermore, direct application of hydrogen peroxide increased BKCa channel activity. Finally, the inhibitory effect of Ang II on the BKCa current was blocked by an antagonist of the Ang II type 1 (AT1) receptor in both control and APE1/Ref-1-overexpressing HUVECs. From these results, we conclude that the inhibitory effect of Ang II on BKCa channel function is NADPH oxidase-dependent and may be promoted by APE1/Ref-1.
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KEYWORD
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Large conductance Ca2+-activated K+ channel, Angiotensin II, Apurinic/apyrimidinic endonuclease1/redox factor 1, Human umbilical vein endothelial cells
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