Author(s): Kuhlmann CR, Gast C, Li F, Schfer M, Tillmanns H,
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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 Ca(2+)-activated K+ channels (BK(Ca)) 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 BK(Ca) were performed on cultured human umbilical vein endothelial cells. NO production was measured using 4,5-diaminofluorescein-fluorescence imaging and a [(3)H]cGMP RIA. Proliferation was analyzed by means of cell counts and [(3)H]thymidine incorporation (TI). Cerivastatin (0.001 to 0.05 micromol/L) caused a significant membrane hyperpolarization (n = 30; P < 0.05). This effect was abolished using the BK(Ca) inhibitor iberiotoxin (IBX; 100 nmol/L). The addition of mevalonate (500 micromol/L) blocked the BK(Ca) activation induced by cerivastatin (n = 19; P < 0.05). Endothelial cGMP level was increased by acetylcholine (ACh; 1 micromol/L). The combination of ACh and cerivastatin additionally increased cGMP levels, with a maximum at 0.03 micromol/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 micro mol/L (cell count, -32.2\%; TI, -70\%; n = 12; P < 0.01). These data show that cerivastatin activates endothelial BK(Ca), which plays an important role in the signaling of cerivastatin-mediated endothelial NO production and proliferation.
This article was published in J Am Soc Nephrol
and referenced in Journal of Nanomedicine & Nanotechnology