A selective matrix metalloproteinase-12 inhibitor retards atherosclerotic plaque development in apolipoprotein E-knockout mice.
A selective matrix metalloproteinase-12 inhibitor retards atherosclerotic plaque development in apolipoprotein E-knockout mice.
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DOI：
10.1161/atvbaha.110.219147
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发表时间：
2011-03
期刊：
影响因子：
--
通讯作者：
Dive V
中科院分区：
文献类型：
--
作者：
Johnson JL;Devel L;Czarny B;George SJ;Jackson CL;Rogakos V;Beau F;Yiotakis A;Newby AC;Dive V
基质金属蛋白酶(MMP12)与斑块的进展和不稳定性有关，也易于选择性抑制。在这项研究中，我们研究了超过10倍的选择性合成的基质金属蛋白酶-12抑制剂对载脂蛋白E基因敲除的动脉粥样硬化模型小鼠斑块进展的影响。一种有效的、选择性的小鼠基质金属蛋白酶-12抑制剂的膦酸肽(RXP470.1)显著减少了喂养西方饮食的雄性和雌性载脂蛋白E基因敲除小鼠4个不同血管部位的动脉粥样硬化斑块横截面积约50%。此外，RXP470.1治疗导致斑块不那么复杂，平滑肌细胞：巨噬细胞比率增加，巨噬细胞凋亡减少，冠层厚度增加，坏死核心变小，钙化发生率降低。此外，体外和体内的研究结果表明，减少单核/巨噬细胞的侵袭和减少巨噬细胞的凋亡可能是使用基质金属蛋白酶-12抑制剂治疗动脉粥样硬化斑块的有益效果的基础。我们的数据表明，一种选择性的基质金属蛋白酶-12抑制剂可以延缓动脉粥样硬化的发展，并导致小鼠出现更多的纤维斑块表型。我们的研究为推动人类基质金属蛋白酶-12抑制剂治疗的翻译工作提供了原则性证据。
Matrix metalloproteinase (MMP)-12 has been implicated in plaque progression and instability and is also amenable to selective inhibition. In this study, we investigated the influence of a greater than 10-fold selective synthetic MMP-12 inhibitor on plaque progression in the apolipoprotein E knockout mouse model of atherosclerosis. A phosphinic peptide (RXP470.1) that is a potent, selective murine MMP-12 inhibitor significantly reduced atherosclerotic plaque cross-sectional area by approximately 50% at 4 different vascular sites in male and female apolipoprotein E knockout mice fed a Western diet. Furthermore, RXP470.1 treatment resulted in less complex plaques with increased smooth muscle cell:macrophage ratio, less macrophage apoptosis, increased cap thickness, smaller necrotic cores, and decreased incidence of calcification. Additional in vitro and in vivo findings indicate that attenuated monocyte/macrophage invasion and reduced macrophage apoptosis probably underlie the beneficial effects observed on atherosclerotic plaque progression with MMP-12 inhibitor treatment. Our data demonstrate that a selective MMP-12 inhibitor retards atherosclerosis development and results in a more fibrous plaque phenotype in mice. Our study provides proof of principle to motivate translational work on MMP-12 inhibitor therapy in humans.