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Cardiovascular Research 2003 60(3):626-634; doi:10.1016/j.cardiores.2003.08.010
© 2003 by European Society of Cardiology
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Copyright © 2003, European Society of Cardiology

Modulation of endothelial Ca2+-activated K+ channels by oxidized LDL and its contribution to endothelial proliferation

Christoph Rüdiger Wolfram Kuhlmanna, Matthias Schäferb, Fang Lia, Tatsuya Sawamurac, Harald Tillmannsa, Bernd Waldeckera and Johannes Wiecha*,d

aDepartment of Cardiology and Angiology, Justus-Liebig-University of Giessen, Germany
bDepartment of Physiology, Justus-Liebig-University of Giessen, Germany
cDepartment of Bioscience, National Cardiovascular Center Research Institute, Osaka, Japan
dDepartment of Internal Medicine, Hospital Bad Orb, Frankfurter Strasse 2, 63619 Bad Orb, Germany

*Corresponding author. Tel.: +49-6052-918370; fax: +49-6052-918371. Email address: dr.johannes.wiecha{at}telemed.de

Objective: Oxidized low-density lipoprotein (oxLDL) plays an important role in causing endothelial dysfunction and initiating atherosclerosis. Some of the endothelial functions have been shown to be modulated by changes in cellular electrophysiological properties. Therefore, we analysed the effect of oxLDL on endothelial Ca2+-activated K+ channels (BKCa) and its contribution to oxLDL-mediated changes of proliferation and syntheses of nitric oxide (NO). Methods: The patch-clamp technique was used to study the behavior of BKCa in human endothelial cells of umbilical cord veins (HUVEC). Changes of intracellular Ca2+ were measured by means of Fura-2 imaging. Cell counts and [3H]-thymidine incorporation were used to analyse endothelial proliferation. Synthesis of NO was measured by means of [3H]-cGMP radioimmunoassay. Results: oxLDL (10 µg/ml) caused a significant increase of BKCa activity, whereas preincubation of HUVEC with an antibody against the lectin-like-oxLDL-receptor-1 (LOX-1) abolished BKCa activation. Fura-2 measurements revealed a biphasic increase of intracellular Ca2+ after application of the atherogenic lipid. Endothelial proliferation was significantly increased by oxLDL. The highly selective BKCa inhibitor iberiotoxin (100 nmol/l IBX) blocked this proliferative response. Acetylcholine-induced NO synthesis was significantly decreased by IBX. Interestingly, oxLDL significantly decreased acetylcholine-induced NO synthesis if the production of superoxide was not blocked by antisense oligonucleotides against the NAD(P)H-oxidase. Conclusions: Our data demonstrate that oxLDL activates BKCa, which plays an important role in oxLDL-mediated endothelial proliferation. Acetylcholine-induced NO synthesis is modulated by BKCa, whereas the reduction of acetylcholine-induced NO-synthesis by oxLDL is related to an increase in superoxide production.

KEYWORDS Lipoproteins; K-channel; Endothelial function; Nitric oxide; Atherosclerosis

Time for primary review 34 days


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