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Abstract
Proliferation of endothelial cells plays a crucial role in the process of atherosclerotic plaque destabilization. The major component of oxidized low-density lipoprotein lysophosphatidylcholine (LPC) has been shown to promote endothelial proliferation by increasing the production of reactive oxygen species (ROS). Since K + channels are known to control the cell cycle, we investigated the role of Ca 2+-activated K + channels (BK Ca) in the regulation of LPC-induced endothelial proliferation and ROS generation. A significant increase of cell growth induced by LPC (20 μmol/l; cell counts (CCs): +87%, thymidin incorporation: +89%; n = 12, P < 0.01) was observed, which was inhibited by the BK Ca inhibitor iberiotoxin (IBX; 100 nmol/l), by the NAD(P)H-oxidase inhibitor diphenyleneiodonium (5 μmol/l) and by transfection with antisense (AS) oligonucleotides against NAD(P)H oxidase, whereas N G-monomethyl- l-arginine ( l-NMMA) further increased LPC-induced cell growth. Using the patch-clamp technique a significant increase of BK Ca open-state probability (control: 0.004 ± 0.002; LPC: 0.104 ± 0.035; n = 21, P < 0.05) by LPC was observed. Using dichlorofluorescein fluorescence microscopy a significant increase of ROS induced by LPC was reported, that was blocked by IBX and Ca 2+ antagonists. Intracellular Ca 2+ measurements revealed a capacitative Ca 2+ influx caused by LPC. Bioactivity of nitric oxide (NO) was measured using a [ 3H]-cGMP radioimmunoassay. LPC significantly decreased acetylcholine-induced NO synthesis. LPC significantly increased cGMP levels in endothelial cells transfected with AS, which was blocked by IBX. In conclusion, our results demonstrate that LPC activates BK Ca thereby increasing ROS production which induces endothelial proliferation. In addition LPC-induced BK Ca-activation contributes to increased cGMP levels, if ROS production is prevented by AS.
Published Version
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