HMG-CoA reductase inhibitors reduce MMP-9 secretion by macrophages
HMG-CoA reductase inhibitors reduce MMP-9 secretion by macrophages
复制标题
DOI：
10.1161/01.atv.18.11.1671
复制
发表时间：
1998-11-01
影响因子：
8.7
通讯作者：
Bernini, F
中科院分区：
文献类型：
--
作者：
Bellosta, S;Via, D;Bernini, F
巨噬细胞分泌基质金属蛋白酶(MMPs)，可能会削弱动脉粥样硬化斑块的纤维帽，使其容易破裂。92 kDa明胶酶B(MMP9)在腹主动脉瘤和动脉粥样硬化组织中已被发现。氟伐他汀通过抑制类异戊二烯途径，在实验模型中抑制动脉粥样硬化形成的主要过程(平滑肌细胞迁移和增殖以及巨噬细胞中胆固醇的积累)。我们研究了氟伐他汀对体外培养的小鼠和人巨噬细胞中基质金属蛋白酶-9活性的影响。用明胶酶谱分析氟伐他汀作用24小时后细胞的条件培养液。在小鼠巨噬细胞中，氟伐他汀(5~100mU·mol/L)对基质金属蛋白酶-9活性的抑制作用呈剂量依赖性，从20%到40%与对照组相比。该药物在低至5微克分子/L的浓度下，对人单核细胞来源的巨噬细胞的基质金属蛋白酶-9活性也有抑制作用(约30%)。佛波酯(TPA，50 ng/mL)可使小鼠和人巨噬细胞的基质金属蛋白酶-9活性增加50%，而氟伐他汀可抑制这一增强活性达50%。Western blotting和ELISA法证实了上述对基质金属蛋白酶-9分泌的影响。同时加入异戊二烯前体甲伐他汀(100mU/L)可克服氟伐他汀的抑制作用。氟伐他汀的作用是完全可逆的，该药物不会造成任何细胞毒性。他汀类药物不能直接阻断分泌的蛋白酶的体外激活。辛伐他汀也获得了类似的数据。总而言之，我们的数据表明该药物对基质金属蛋白酶-9的分泌有抑制作用。这种作用是通过抑制甲氧戊酸的合成来实现的，甲氧戊酸是多种细胞功能所必需的多种衍生物的前体。
Macrophages secrete matrix metalloproteinases (MMPs) that may weaken the fibrous cap of atherosclerotic plaque, predisposing its fissuration. The 92-kDa gelatinase B (MMP-9) has been identified in abdominal aortic aneurysms and in atherosclerotic tissues. Fluvastatin, through the inhibition of the isoprenoid pathway, inhibits major processes of atherogenesis in experimental models (smooth muscle cell migration and proliferation and cholesterol accumulation in macrophages). We studied the effect of fluvastatin on the activity of MMP-9 in mouse and human macrophages in culture. Conditioned media of cells treated for 24 hours with fluvastatin were analyzed by gelatin zymography. In mouse macrophages, fluvastatin (5 to 100 mu mol/L) significantly inhibited in a dose-dependent manner MMP-9 activity from 20% to 40% versus control. The drug, at a concentration as low as 5 mu mol/L, inhibited MMP-9 activity ( approximate to 30%) in human monocyte-derived macrophages as well. Phorbol esters (TPA, 50 ng/mL) stimulated MMP-9 activity by 50%, and fluvastatin inhibited this enhanced activity up to 50% in both mouse and human macrophages. The above results on the secretion of MMP-9 were confirmed by Western blotting and ELISA. The inhibitory effect of fluvastatin was overcome by the simultaneous addition of exogenous mevalonate (100 mu mol/L), a precursor of isoprenoids. Fluvastatin's effect was fully reversible, and the drug did not cause any cellular toxicity. The statin did not block directly the in vitro activation of the secreted protease. Similar data were obtained with simvastatin. Altogether our data indicate an inhibition of MMP-9 secretion by the drug. This effect is mediated by the inhibition of synthesis of mevalonate, a precursor of numerous derivatives essential for several cellular functions.