Treharne G D, Boyle J R, Goodall S, Loftus I M, Bell P R, Thompson M M
Department of Vascular Surgery, Robert Kilpatrick Clinical Sciences Building, Leicester Royal Infirmary, Leicester LE2 7LX, UK.
Br J Surg. 1999 Aug;86(8):1053-8. doi: 10.1046/j.1365-2168.1999.01196.x.
Abdominal aortic aneurysms are characterized by degradation of the extracellular matrix, with a reduction in the elastin concentration of the arterial media. These changes have been linked to increased levels of endogenous metalloproteinases (MMPs) within the aorta, particularly MMP-2 and MMP-9. This provides a potential therapeutic target for pharmacological agents aimed at reducing the growth rate of small aneurysms. In this study, the ability of marimastat (an MMP inhibitor) to reduce matrix degradation was assessed in a previously described model of aneurysm disease.
Porcine aortic segments (n = 12) were preincubated in exogenous pancreatic elastase for 24 h before culture in standard conditions for 13 days with marimastat 10(-5), 10(-6) and 10(-7) mol/l. Control segments were cultured both without marimastat and without elastase. At the termination of culture, MMPs were extracted from the tissue and quantified by substrate gel enzymography. The volume fractions of elastin and collagen were determined by stereological analysis of sections stained with Miller's elastin and van Gieson's stain.
Stereological analysis demonstrated preservation of elastin in aorta treated with marimastat at 10(-6) and 10(-5) mol/l; this was significant at the latter concentration (P = 0.007). This was accompanied by a significant reduction in active MMP-2 activity in the samples treated with marimastat 10(-5) mol/l (P < 0.01).
Marimastat significantly inhibited elastin degradation and active MMP-2 production within aortic organ cultures.
腹主动脉瘤的特征是细胞外基质降解，动脉中膜弹性蛋白浓度降低。这些变化与主动脉内源性金属蛋白酶（MMPs）水平升高有关，尤其是MMP - 2和MMP - 9。这为旨在降低小动脉瘤生长速度的药物提供了潜在的治疗靶点。在本研究中，在先前描述的动脉瘤疾病模型中评估了马立马司他（一种MMP抑制剂）减少基质降解的能力。
将猪主动脉段（n = 12）在外源性胰弹性蛋白酶中预孵育24小时，然后在标准条件下用10(-5)、10(-6)和10(-7) mol/l的马立马司他培养13天。对照段在无马立马司他和无弹性蛋白酶的条件下培养。培养结束时，从组织中提取MMPs并通过底物凝胶酶谱法进行定量。通过对用米勒弹性蛋白染色和范吉森染色的切片进行体视学分析来测定弹性蛋白和胶原蛋白的体积分数。
体视学分析表明，用10(-6)和10(-5) mol/l马立马司他处理的主动脉中弹性蛋白得以保留；在后者浓度下这一结果具有显著性（P = 0.007）。同时，用10(-5) mol/l马立马司他处理的样品中活性MMP - 2活性显著降低（P < 0.01）。
马立马司他在主动脉器官培养中显著抑制弹性蛋白降解和活性MMP - 2的产生。
