Doxycycline inhibits elastin degradation and reduces metalloproteinase activity in a model of aneurysmal disease
Doxycycline inhibits elastin degradation and reduces metalloproteinase activity in a model of aneurysmal disease
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DOI：
10.1016/s0741-5214(98)70367-2
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发表时间：
1998-02-01
影响因子：
4.3
通讯作者：
Thompson, MM
中科院分区：
文献类型：
--
作者：
Boyle, JR;McDermott, E;Thompson, MM
目的：腹主动脉瘤的特征是细胞外基质降解，动脉介质弹性蛋白浓度降低。这些变化是由主动脉内内源性金属蛋白酶（MMP）水平升高介导的，这为旨在降低小动脉瘤生长速率的药物提供了潜在的治疗靶点。在这项研究中，在先前描述的动脉瘤疾病模型中评估了强力霉素（MMP释放剂）减少基质降解的能力，该模型使用弹性蛋白酶的短暂脉冲来诱导动脉器官培养物中MMP的产生和弹性蛋白降解。猪主动脉节段（n = 8）在外源性胰腺弹性蛋白酶中预孵育24小时，然后在标准条件下用1和10 mg/L多西环素培养13天。对照节段在没有强力霉素和没有弹性蛋白酶的情况下培养。在培养结束时，从组织中提取MMPs，并通过底物凝胶酶谱和免疫印迹的组合进行定量。弹性蛋白和胶原的体积分数通过体视学分析的切片染色与米勒的弹性蛋白和货车Gieson的stain.Results：体视学分析表明，一个显着的保存弹性蛋白在主动脉与强力霉素10 mg/L（p < 0.001），并表明，这种保存伴随着MMP-9活性的显着降低（p < 0.02）。金属蛋白酶的组织抑制剂（TIMP-1和TIMP-2）的免疫印迹显示没有减少生产的多西环素治疗groups.Conclusions：治疗范围的多西环素显着抑制弹性蛋白降解和MMP-9的生产主动脉器官培养。这些数据表明，多西环素可能有一个潜在的应用，在减少小腹主动脉瘤的生长速度。
Purpose: Abdominal aortic aneurysms are characterized by degradation of the extracellular matrix, with a reduction in the elastin concentration of the arterial media. These changes are mediated by increased levels of endogenous metalloproteinases (MMPs) within the aorta, which provide a potential therapeutic target for pharmacologic agents aimed at reducing the growth rate of small aneurysms. In this study, the ability of doxycycline-an MMP inhibitor-to reduce matrix degradation was assessed in a previously described model of aneurysmal disease that used a brief pulse of elastase to induce MMP production and elastin degradation in arterial organ cultures.Methods: Porcine aortic segments (n = 8) were preincubated in exogenous pancreatic elastase for 24 hours before culture in standard conditions for 13 days with both 1 and 10 mg/L doxycycline. Control segments were cultured both without doxycycline and without elastase. At the termination of culture, MMPs were extracted from the tissue and quantified by a combination of substrate gel enzymography and immunoblotting. The volume fractions of elastin and collagen were determined by stereologic analysis of sections stained with Miller's elastin and van Gieson's stain.Results: Stereologic analysis demonstrated a significant preservation of elastin in aorta treated with doxycycline 10 mg/L (p < 0.001) and demonstrated that this preservation was accompanied by a significant reduction in MMP-9 activity (p < 0.02). Immunoblotting for tissue inhibitors of metalloproteinases (TIMP-1 and TIMP-2) showed no decreased production in the doxycycline-treated groups.Conclusions: Therapeutic ranges of doxycycline significantly inhibited elastin degradation and MMP-9 production within aortic organ cultures. These data suggest that doxycycline may have a potential application in reducing the growth rates of small abdominal aortic aneurysms.