Evidence for altered balance between matrix metalloproteinases and their inhibitors in human aortic diseases
Evidence for altered balance between matrix metalloproteinases and their inhibitors in human aortic diseases
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DOI：
10.1161/01.cir.95.1.205
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发表时间：
1997-01-07
期刊：
影响因子：
37.8
通讯作者：
Libby, P
中科院分区：
文献类型：
--
作者：
Knox, JB;Sukhova, GK;Libby, P
背景 尽管腹主动脉瘤 (AAA) 表现出基质金属蛋白酶 (MMP) 表达增加，但 MMP 及其组织抑制剂 (TIMP) 之间的功能平衡仍不确定。本报告采用新型原位酶谱技术比较了正常主动脉、主动脉闭塞性疾病 (AOD) 和 AAA 的蛋白水解活性。方法和结果从 25 名接受 AOD 或 AAA 手术的患者身上获取肾下主动脉标本，并与从尸体获取的正常主动脉组织 (n=7) 进行比较。对胶原酶 (MMP-1)、明胶酶 A (MMP-2)、溶基质素 (MMP-3)、TIMP-1 和 TIMP-2 进行免疫组织化学染色。通过原位酶谱法测定净蛋白水解活性，其中主动脉切片在荧光标记的底物上孵育。在落射荧光检查下检测蛋白水解活性。与正常主动脉组织相比，AOD 和 AAA 组织的 MMP-1 和 MMP-3 免疫反应性显着增加（主要在新内膜中），而 TIMP-1 则适度增加。 MMP-2 在患病主动脉中增加，TIMP-2 在正常、AOD 和 AAA 样本中丰富。酶谱分析揭示了 AOD 和 AAA 组织中的蛋白水解活性，可主动消化酪蛋白和明胶底物，特别是在样本的管腔部分。正常标本不表现出裂解活性。 AOD和AAA样本的比较显示MMP/TIMP免疫反应性或净蛋白水解活性没有差异。结论AOD和AAA样本中MMP表达显着增加，MMP及其抑制剂之间的不平衡导致相似的蛋白水解活性。动脉瘤或闭塞性病变的最终形成似乎不是由蛋白水解模式的持续差异引起的。
Background Although abdominal aortic aneurysms (AAAs) exhibit increased expression of matrix metalloproteinases (MMPs), the functional balance between MMPs and their tissue inhibitors (TIMPs) remains uncertain. This report compares the proteolytic activity in normal aorta, aorto-occlusive disease (AOD), and AAA by use of a novel in situ zymographic technique.Methods and Results Infrarenal aortic specimens were obtained from 25 patients undergoing surgery for AOD or AAA and were compared with normal aortic tissue (n=7) obtained from cadavers. Immunohistochemical staining was performed for collagenase (MMP-1), gelatinase A (MMP-2), stromelysin (MMP-3), TIMP-1, and TIMP-2. Net proteolytic activity was determined with in situ zymography whereby aortic sections were incubated on fluorescently labeled substrate. Proteolytic activity was detected under epifluorescent examination. Compared with normal aortic tissue, AOD and AAA tissue demonstrated marked increases in MMP-1 and MMP-3 immunoreactivity, predominantly in the neointima, and modest increases in TIMP-1. MMP-2 was increased in the diseased aortas, and TIMP-2 was abundant in normal, AOD, and AAA samples. Zymography revealed proteolytic activity in AOD and AAA tissues with active digestion of casein and gelatin substrate, particularly on the luminal portion of the specimens. Normal specimens exhibited no lytic activity. Comparison of AOD and AAA specimens revealed no difference in MMP/TIMP immunoreactivity or net proteolytic activity.Conclusions MMP expression is markedly increased in AOD and AAA samples, and an imbalance between MMPs and their inhibitors results in similar proteolytic activity. The eventual formation of aneurysmal or occlusive lesions appears not to result from an ongoing difference in the proteolytic pattern.