Hypercholesterolemia inhibits L-type calcium current in coronary macro-, not microcirculation
Hypercholesterolemia inhibits L-type calcium current in coronary macro-, not microcirculation
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DOI：
10.1152/japplphysiol.01229.2003
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发表时间：
2004-06-01
影响因子：
3.3
通讯作者：
Price, EM
中科院分区：
文献类型：
--
作者：
Bowles, DK;Heaps, CL;Price, EM
高胆固醇血症(HC)是冠心病发生的主要危险因素。冠状动脉离子调节，尤其是钙离子调节在冠心病的发生发展中起重要作用；然而，高脂肪和高胆固醇对冠状动脉平滑肌(CASM)离子通道的影响尚不清楚。本研究的目的是确定饮食诱导的HC对CASM电压门控钙电流(I-Ca)的影响。雄性小型猪饲喂高脂、高胆固醇日粮(40%卡路里脂肪，2%wt胆固醇)20-24 wk，导致血清总胆固醇和低密度脂蛋白胆固醇升高。组织化学显示大冠状动脉早期出现动脉粥样硬化。CASM分离自右冠状动脉(>；1.0 mm内径)、小动脉(类似于200um)和大小动脉(类似于100um)。采用全细胞电压钳技术测定细胞内钙离子浓度。与对照组相比，HC可使右冠状动脉L型钙通道减少30%(-5.29+/-0.42vs.-7.59+/-0.41pA/pF)，但不影响微循环(小动脉，-8.39+/-0.80vs.-10.13+/-0.60；小动脉，-10.78+/-0.93vs.-11.31+/-0.95pA/pF)。在大循环和微循环中，HC均不影响电压依赖性激活。HC对L型电压门控性钙通道(Ca(V)1.2m RNA和膜蛋白水平无明显影响。在体外，胆固醇清除剂甲基-β-环糊精可逆转HC对钙离子的抑制作用，并通过与胆固醇供体胆固醇：甲基-β-环糊精孵育来模拟对照CASM。提示动脉粥样硬化早期冠状动脉大血管L型钙离子浓度降低，而微循环中钙离子浓度无明显变化。大冠状动脉CASM中钙通道活性的抑制可能是由于膜上游离胆固醇增加所致。
Hypercholesterolemia (HC) is a primary risk factor for the development of coronary heart disease. Coronary ion regulation, especially calcium, is thought to be important in coronary heart disease development; however, the influence of high dietary fat and cholesterol on coronary arterial smooth muscle (CASM) ion channels is unknown. The purpose of this study was to determine the effect of diet-induced HC on CASM voltage-gated calcium current (I-Ca). Male miniature swine were fed a high-fat, high-cholesterol diet (40% kcal fat, 2% wt cholesterol) for 20-24 wk, resulting in elevated serum total and low-density lipoprotein cholesterol. Histochemistry indicated early atherosclerosis in large coronary arteries. CASM were isolated from the right coronary artery (>1.0 mm ID), small arteries (similar to200 mum), and large arterioles (similar to100 mum). I-Ca was determined by whole cell voltage clamp. L-type I-Ca was reduced similar to30% by HC compared with controls in the right coronary artery (-5.29+/-0.42 vs. -7.59+/-0.41 pA/pF) but not the microcirculation (small artery, -8.39+/-0.80 vs. -10.13+/-0.60; arterioles, -10.78+/-0.93 vs. -11.31+/-0.95 pA/pF). Voltage-dependent activation was unaffected by HC in both the macro- and microcirculation. L-type voltage-gated calcium channel (Ca(v)1.2) mRNA and membrane protein levels were unaffected by HC. Inhibition of I-Ca by HC was reversed in vitro by the cholesterol scavenger methyl-beta-cyclodextrin and mimicked in control CASM by incubation with the cholesterol donor cholesterol: methyl-beta-cyclodextrin. These data indicate that CASM L-type I-Ca is decreased in large coronary arteries in early stages of atherosclerosis, whereas I-Ca in the microcirculation is unaffected. The inhibition of calcium channel activity in CASM of large coronary arteries is likely due to increases in membrane free cholesterol.