APE1/Ref-1 Promotes the Effect of Angiotensin II on Ca(2+)-Activated K(+) Channel in Human Endothelial Cells via Suppression of NADPH Oxidase

作者：Park Won Sun; Ko Eun A; Jung In Duk; Son Youn Kyoung; Kim Hyoung Kyu; Kirn Nari; Park So Youn; Hong Ki Whan; Park Yeong Min; Choi The Hoon; Han Jin^*

来源：Archives of Pharmacal Research, 2008, 31(10): 1291-1301.

DOI：10.1007/s12272-001-2109-y

• Large conductance Ca(2+)-activated K(+) channel
• Angiotensin II
• Apurinic/apyrimidinic
• endonucleasel/redox factor 1
• Human umbilical vein endothelial cells

The effects of angiotensin II (Ang II) on whole-cell large conductance Ca(2+)-activated K(+) (BK(Ca))currents was investigated in control and Apurinic/apyrimidinic endonuclease 1 /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 BK(Ca) 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 BK(Ca) current was blocked by an antagonist of the Ang II type I (AT,) 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.

• 出版日期2008-10