EFFECTS OF 26-AMINOCHOLESTEROL, 27-HYDROXYCHOLESTEROL, AND 25-HYDROXYCHOLESTEROL ON PROLIFERATION AND CHOLESTEROL HOMEOSTASIS IN ARTERIAL MYOCYTES
EFFECTS OF 26-AMINOCHOLESTEROL, 27-HYDROXYCHOLESTEROL, AND 25-HYDROXYCHOLESTEROL ON PROLIFERATION AND CHOLESTEROL HOMEOSTASIS IN ARTERIAL MYOCYTES
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DOI：
10.1161/01.atv.15.3.420
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发表时间：
1995-03-01
影响因子：
8.7
通讯作者：
FUMAGALLI, R
中科院分区：
文献类型：
--
作者：
CORSINI, A;VERRI, D;FUMAGALLI, R
细胞生长和胆固醇稳态之间存在的主要关系促使我们研究26-氨基胆固醇（26-NH 2），27-羟基胆固醇（27-OH）和25-羟基胆固醇（25-OH）对这些细胞事件的影响。为了测试这种关系，我们将人和大鼠的动脉肌细胞与固醇一起孵育72小时。所有测试的化合物（0.5至7.5 μ mol/L）抑制大鼠和人心肌细胞增殖和胆固醇生物合成的剂量依赖性方式。26-NH 2在抑制人肌细胞增殖方面比氧固醇更有效，但在大鼠细胞中效果相同; 27-OH和25-OH在两种细胞系中显示出相似的活性。抑制大鼠心肌细胞中胸苷的核掺入与细胞计数减少一致。所测试的固醇的抗增殖作用是可逆的。诱导肌细胞增殖减少所必需的胆固醇生物合成的高抑制（80%）表明胆固醇合成途径与这些细胞过程之间存在因果关系。此外，所有测试的甾醇能够抑制羟甲基戊二酰辅酶A还原酶活性在完整的心肌细胞，但不是在无细胞提取物。26-NH 2而不是27-OH或25-OH不抑制人或大鼠心肌细胞中的LDL受体活性的发现支持了对协同调节的LDL受体基因的选择性的实现。26-NH 2干扰肌细胞增殖和胆固醇合成而不影响LDL受体途径的能力至少在体外赋予了该化合物在动脉粥样硬化形成过程中的药理学意义。
The major relation existing between cell growth and cholesterol homeostasis prompted us to investigate the effect of 26-aminocholesterol (26-NH2), 27-hydroxycholesterol (27-OH), and 25-hydroxycholesterol (25-OH) on these cellular events. To test this relation, we incubated human and rat arterial myocytes with the sterols for 72 hours. All the tested compounds (0.5 to 7.5 mu mol/L) inhibited rat and human myocyte proliferation and cholesterol biosynthesis in a dose-dependent manner. 26-NH2 was more potent than oxysterols in inhibiting human myocyte proliferation but equieffective in rat cells; 27-OH and 25-OH displayed similar activity in both cell lines. Inhibition of nuclear incorporation of thymidine in rat myocytes is consistent with decreased cell count. The antiproliferative effect of the tested sterols was reversible. The high inhibition (80%) of cholesterol biosynthesis necessary to induce a decrease in myocyte proliferation suggests a causal relation between the cholesterol synthetic pathway and these cellular processes. In addition, all the tested sterols were able to inhibit hydroxymethyl glutaryl-coenzyme A reductase activity in intact myocytes but not in cell-free extracts. The finding that 26-NH2 but not 27-OH or 25-OH does not suppress LDL receptor activity in either human or rat myocytes supports the achievement of selectivity over the coordinately regulated LDL receptor gene. The ability of 26-NH2 to interfere with myocyte proliferation and cholesterol synthesis without affecting the LDL receptor pathway confers at least in vitro a pharmacological interest on the compound in the process of atherogenesis.