Modulation by simvastatin of iberiotoxin-sensitive, Ca2+-activated K+ channels of porcine coronary artery smooth muscle cells
Modulation by simvastatin of iberiotoxin-sensitive, Ca2+-activated K+ channels of porcine coronary artery smooth muscle cells
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DOI：
10.1038/sj.bjp.0707327
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发表时间：
2007-08-01
影响因子：
7.3
通讯作者：
Kwan, Y. W.
中科院分区：
文献类型：
--
作者：
Seto, S. W.;Au, A. L. S.;Kwan, Y. W.
背景和目的：他汀类药物(3-羟基-3-甲基戊二酰辅酶A(HMG CoA)还原酶抑制剂)已被证明可降低心血管死亡率。目前尚不清楚HMG CoA还原酶在心血管组织中的表达水平与来自肝脏的细胞中的表达水平相比如何。我们假设该酶存在于不同的心血管组织中，辛伐他汀对血管内毒素敏感的钙激活钾(BKCa)通道具有调节作用。实验方法：检测HMG CoA还原酶在不同心血管制剂中的表达。研究辛伐他汀对猪冠状动脉平滑肌细胞BKCa通道蛋白表达的影响。关键结果：免疫印迹显示人心血管组织和猪冠状动脉组织中存在HMG CoA还原酶。在猪冠状动脉平滑肌细胞上，胞外辛伐他汀(1、3和10mU M)(疏水性)抑制BKCa通道，但不抑制Na+(亲水性)，洗脱后恢复最小。外用辛伐他汀可逆转异海松酸(10mU M)对BKCa幅度的增强作用。辛伐他汀钠离子(10 mM，内服)可显著减弱异海马酸(10 MM)引起的BKCa波幅增强。还原型谷胱甘肽(5 mM；在移液管溶液中)可消除辛伐他汀引起的抑制。美瓦隆内酯(500 MM)和香叶基焦磷酸香叶素(20mM)仅能阻止辛伐他汀(1mM和3mM)诱导的反应。辛伐他汀(10MU M)可引起ROTTLER(1MU M)敏感(环己亚胺(10MU M)不敏感)PKC-Delta蛋白表达增加。结论和意义：我们的结果证实了HMG CoA还原酶在不同的心血管组织中的生化存在，辛伐他汀通过多个细胞内途径抑制动脉平滑肌细胞的BKCa通道。
Background and Purpose: Statins (3-hydroxy-3-methyl-glutaryl coenzyme A (HMG CoA) reductase inhibitors) have been demonstrated to reduce cardiovascular mortality. It is unclear how the expression level of HMG CoA reductase in cardiovascular tissues compares with that in cells derived from the liver. We hypothesized that this enzyme exists in different cardiovascular tissues, and simvastatin modulates the vascular iberiotoxin-sensitive Ca2+ activated K+ (BKCa) channels.Experimental Approaches: Expression of HMG CoA reductase in different cardiovascular preparations was measured. Effects of simvastatin on BKCa channel gatings of porcine coronary artery smooth muscle cells were evaluated.Key Results: Western immunoblots revealed the biochemical existence of HMG CoA reductase in human cardiovascular tissues and porcine coronary artery. In porcine coronary artery smooth muscle cells, extracellular simvastatin (1, 3 and 10 mu M) (hydrophobic), but not simvastatin Na+ (hydrophilic), inhibited the BKCa channels with a minimal recovery upon washout. Isopimaric acid (10 mu M)-mediated enhancement of the BKCa amplitude was reversed by external simvastatin. Simvastatin Na+ (10 mu M, applied internally), markedly attenuated isopimaric acid (10 mM)-induced enhancement of the BKCa amplitude. Reduced glutathione (5 mM; in the pipette solution) abolished simvastatin-elicited inhibition. Mevalonolactone (500 mM) and geranylgeranyl pyrophosphate (20 mu M) only prevented simvastatin (1 and 3 mu M)-induced responses. simvastatin (10 mu M) caused a rottlerin (1 mu M)-sensitive (cycloheximide (10 mu M)-insensitive) increase of PKC-delta protein expression.Conclusions and Implications: Our results demonstrated the biochemical presence of HMG CoA reductase in different cardiovascular tissues, and that simvastatin inhibited the BKCa channels of the arterial smooth muscle cells through multiple intracellular pathways.