Cerivastatin Activates Endothelial Calcium–Activated Potassium Channels and Thereby Modulates Endothelial Nitric Oxide Production and Cell Proliferation

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Abstract
Statins are known to counteract the process of arteriosclerosis by exerting direct pleiotropic effects on vascular endothelium. The aim of this study was to investigate a possible effect of cerivastatin on endothelial Ca2+-activated K+ channels (BKCa) and to assess their contribution to cerivastatin-mediated changes of endothelial nitric oxide (NO) production and proliferation. Membrane potential was measured using bis-1,3-dibutylbarbituric acid-trimethine oxonol–fluorescence imaging. Patch-clamp recordings of BKCa were performed on cultured human umbilical vein endothelial cells. NO production was measured using 4,5-diaminofluorescein–fluorescence imaging and a [3H]cGMP RIA. Proliferation was analyzed by means of cell counts and [3H]thymidine incorporation (TI). Cerivastatin (0.001 to 0.05 μmol/L) caused a significant membrane hyperpolarization (n = 30; P < 0.05). This effect was abolished using the BKCa inhibitor iberiotoxin (IBX; 100 nmol/L). The addition of mevalonate (500 μmol/L) blocked the BKCa activation induced by cerivastatin (n = 19; P < 0.05). Endothelial cGMP level was increased by acetylcholine (ACh; 1 μmol/L). The combination of ACh and cerivastatin additionally increased cGMP levels, with a maximum at 0.03 μmol/L cerivastatin (84%; n = 10, P < 0.01). ACh-induced increase of cGMP-level was significantly reduced by IBX (n = 10, P < 0.01) as it was with all combined administrations of ACh and cerivastatin. 4,5-Diaminofluorescein–fluorescence measurements revealed a significant increase of NO levels by cerivastatin, which was abolished by IBX (n = 30; P < 0.05). Cell counts and TI demonstrated significant inhibition of human umbilical vein endothelial cell proliferation with a maximum at 0.03 μmol/L (cell count, −32.2%; TI, −70%; n = 12; P < 0.01). These data show that cerivastatin activates endothelial BKCa, which plays an important role in the signaling of cerivastatin-mediated endothelial NO production and proliferation.