Rosuvastatin reduces MMP-7 secretion by human monocyte-derived macrophages: potential relevance to atherosclerotic plaque stability
Rosuvastatin reduces MMP-7 secretion by human monocyte-derived macrophages: potential relevance to atherosclerotic plaque stability
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DOI：
10.1016/j.atherosclerosis.2004.01.009
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发表时间：
2004-05-01
期刊：
影响因子：
5.3
通讯作者：
Rouis, M
中科院分区：
文献类型：
--
作者：
Furman, C;Copin, C;Rouis, M
3-羟基-3-甲基戊二酰辅酶 A (HMG-CoA) 还原酶抑制剂（他汀类药物）已被证明可以通过其对致动脉粥样化脂质谱的作用和多效性作用来降低心血管发病率和死亡率。在这项研究中，我们研究了一种新型他汀类药物瑞舒伐他汀 (Crestoro) 对人单核细胞源性巨噬细胞 (HMDM) 中甾醇合成和金属蛋白酶 (MMP) 表达的影响。 Rosuvastatin 剂量依赖性地抑制乙酸盐合成甾醇，IC50 为 70 nM。此外，MMP-7 水平以剂量依赖性方式降低，1 μM 时最大抑制率为 50% (P < 0.01)。此外，添加类异戊二烯如法呢基焦磷酸（Fpp）或香叶基香叶基焦磷酸（GGpp）完全克服了瑞舒伐他汀对MMP-7的抑制作用。在用瑞舒伐他汀 (10(-6) M) 处理后，定量 PCR 或用人 MMP-7 启动子（MMP-7 基因 5' 区域的 2300 bp）控制下的荧光素酶报告构建体瞬时转染 HMDM 均未显示 MMP-7 mRNA 减少。然而，根据放线菌素D实验测定，他汀类药物的抑制作用发生在转录后水平。总之，多项研究报告称，活性 MMP-7 在人类动脉粥样硬化斑块中高表达，表明其在削弱纤维帽、使其易于破裂方面具有潜在作用。瑞舒伐他汀减少 MMP-7 的作用可能会保护纤维帽免于降解，进而稳定动脉粥样硬化斑块。 (C) 2004 Elsevier Ireland Ltd. 保留所有权利。
3-Hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins) have been shown to reduce cardiovascular morbidity and mortality by their actions on atherogenic lipid profiles and by pleiotropic effects. In this study, we have investigated the effect of a new statin, rosuvastatin (Crestoro), on sterol synthesis and the expression of metalloproteinases (MMPs) in human monocyte-derived macrophages (HMDM). Rosuvastatin dose-dependently inhibited sterol synthesis from acetate with an IC50 of 70 nM. In addition, MMP-7 levels were reduced in a dose-dependent manner with maximal inhibition of 50% (P < 0.01) at 1 muM. Also, addition of isoprenoids such as farnesyl pyrophosphate (Fpp) or geranylgeranyl pyrophosphate (GGpp) fully overcame the inhibitory effect of rosuvastatin on MMP-7. Neither quantitative PCR nor transient transfection of HMDM with a luciferase reporter construct under the control of human MMP-7 promoter (2300 bp of the 5' region on MMP-7 gene) showed a decrease in MMP-7 mRNA following treatment with rosuvastatin (10(-6) M). However, the inhibitory effect of the statin occurred at the post-transcriptional level as determined by actinomycin D experiment. In conclusion, several studies have reported a high expression of active MMP-7 in human atherosclerotic plaques indicating a potential role in the weakening of the fibrous cap, predisposing it to rupture. The effect of rosuvastatin in reducing MMP-7 might protect fibrous caps from degradation and in turn stabilize atheromatous plaques. (C) 2004 Elsevier Ireland Ltd. All rights reserved.