Institute of Atherosclerosis, Taishan Medical University, Taian, Shandong 271000, China.
Lipids Health Dis. 2011 Jan 18;10:8. doi: 10.1186/1476-511X-10-8.
Statins are first-line pharmacotherapeutic agents for hypercholesterolemia treatment in humans. However the effects of statins on atherosclerosis in mouse models are very paradoxical. In this work, we wanted to evaluate the effects of simvastatin on serum cholesterol, atherogenesis, and the expression of several factors playing important roles in reverse cholesterol transport (RCT) in apoE-/- mice fed a high-fat diet.
The atherosclerotic lesion formation displayed by oil red O staining positive area was reduced significantly by 35% or 47% in either aortic root section or aortic arch en face in simvastatin administrated apoE-/- mice compared to the control. Plasma analysis by enzymatic method or ELISA showed that high-density lipoprotein-cholesterol (HDL-C) and apolipoprotein A-I (apoA-I) contents were remarkably increased by treatment with simvastatin. And plasma lecithin-cholesterol acyltransferase (LCAT) activity was markedly increased by simvastatin treatment. Real-time PCR detection disclosed that the expression of several transporters involved in reverse cholesterol transport, including macrophage scavenger receptor class B type I, hepatic ATP-binding cassette (ABC) transporters ABCG5, and ABCB4 were induced by simvastatin treatment, the expression of hepatic ABCA1 and apoA-I, which play roles in the maturation of HDL-C, were also elevated in simvastatin treated groups.
We demonstrated the anti-atherogenesis effects of simvastatin in apoE-/- mice fed a high-fat diet. We confirmed here for the first time simvastatin increased the expression of hepatic ABCB4 and ABCG5, which involved in secretion of cholesterol and bile acids into the bile, besides upregulated ABCA1 and apoA-I. The elevated HDL-C level, increased LCAT activity and the stimulation of several transporters involved in RCT may all contribute to the anti-atherosclerotic effect of simvastatin.
他汀类药物是人类治疗高胆固醇血症的一线药物。然而，他汀类药物在小鼠模型中的抗动脉粥样硬化作用却非常矛盾。在这项工作中，我们想评估辛伐他汀对高脂饮食喂养的 apoE-/- 小鼠血清胆固醇、动脉粥样硬化形成和几种在胆固醇逆向转运 (RCT) 中起重要作用的因子表达的影响。
辛伐他汀处理的 apoE-/- 小鼠主动脉根部切片或主动脉弓正面的油红 O 染色阳性面积的动脉粥样硬化病变形成减少了 35%或 47%。酶法或 ELISA 法血浆分析显示，高密度脂蛋白胆固醇 (HDL-C) 和载脂蛋白 A-I (apoA-I) 含量显著增加。辛伐他汀治疗后血浆卵磷脂胆固醇酰基转移酶 (LCAT) 活性明显增加。实时 PCR 检测显示，几种参与胆固醇逆向转运的转运蛋白的表达，包括巨噬细胞清道夫受体 B 型 I、肝 ATP 结合盒 (ABC) 转运体 ABCG5 和 ABCB4，由辛伐他汀处理诱导，肝 ABCA1 和 apoA-I 的表达，在 HDL-C 成熟中起作用，也在辛伐他汀处理组中升高。
我们证明了辛伐他汀在高脂饮食喂养的 apoE-/- 小鼠中的抗动脉粥样硬化作用。我们首次证实辛伐他汀增加了肝 ABCB4 和 ABCG5 的表达，这涉及胆固醇和胆汁酸分泌到胆汁中，此外还上调了 ABCA1 和 apoA-I。升高的 HDL-C 水平、增加的 LCAT 活性和刺激几种参与 RCT 的转运蛋白可能都有助于辛伐他汀的抗动脉粥样硬化作用。
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