升主动脉瘤发展中的一个潜在关键机制：检测 MMP-14/TIMP-2 比值与活性 MMP-2 之间的线性关系。
A potential key mechanism in ascending aortic aneurysm development: Detection of a linear relationship between MMP-14/TIMP-2 ratio and active MMP-2.
机构信息
Department of Cardiovascular Surgery, University Heart Center Freiburg-Bad Krozingen, University of Freiburg, Freiburg, Germany.
Faculty of Medicine, University of Freiburg, Freiburg, Germany.
出版信息
PLoS One. 2019 Feb 22;14(2):e0212859. doi: 10.1371/journal.pone.0212859. eCollection 2019.
OBJECTIVES
Elevated matrix metalloproteinase-2 (MMP-2) tissue levels have been associated with ascending thoracic aortic aneurysm (aTAA). As MMP-2 activation is controlled by interactions among matrix metalloproteinase-14 (MMP-14), a tissue inhibitor of metalloproteinases-2 (TIMP-2) and Pro-MMP-2 in cell culture, this activation process might also play a role in aTAA.
METHODS
Via gelatin zymography we analyzed tissue levels of MMP-2 isoforms (Pro-MMP-2, active MMP-2, total MMP-2) and via enzyme-linked immunosorbent assay (ELISA,) MMP-14,TIMP-2 and total MMP-2 tissue levels in N = 42 patients with aTAA. As controls, MMP-14 and TIMP-2 aortic tissue levels in N = 9 patients undergoing coronary artery bypass surgery were measured via ELISA, and levels of MMP-2 isoforms in N = 11 patients via gelatin zymography.
RESULTS
Active MMP-2 was significantly higher in aTAA than in controls. Patients with aTAA exhibited significantly lower Pro-MMP-2 and TIMP-2 levels. Total MMP-2 and MMP-14 did not differ significantly between groups. Regression analysis revealed a linear relationship between TIMP-2 and the MMP-14/TIMP-2 ratio, as well as active MMP-2 in aTAA. Aneurysmatic tissue can be accurately distinguished from control aortic tissue (AUC = 1) by analyzing the active MMP-2/Pro-MMP-2 ratio with a cutoff value of 0.11, whereas MMP-14 and TIMP-2 roles are negligible in ROC analysis.
CONCLUSION
A larger amount of MMP-2 is activated in aTAA than in control aortic tissue-a factor that seems to be a central process in aneurysm development. When active MMP-2 exceeds 10% compared to Pro-MMP-2, we conclude that it originates from aneurysmatic tissue, which we regard as a starting point for further studies of aTAA biomarkers. The tissue's MMP-14/TIMP-2 ratio may regulate the degree of Pro-MMP-2 activation as a determining factor, while the enzymatic activities of MMP-14 and TIMP-2 do not seem to play a key role in aneurysm development.
目的
已有研究表明，基质金属蛋白酶-2（MMP-2）组织水平升高与升主动脉瘤（aTAA）有关。在细胞培养中，MMP-2 的激活受到基质金属蛋白酶-14（MMP-14）、基质金属蛋白酶抑制剂-2（TIMP-2）和前基质金属蛋白酶-2（Pro-MMP-2）之间相互作用的控制，因此该激活过程也可能在 aTAA 中发挥作用。
方法
通过明胶酶谱法分析了 42 例 aTAA 患者的 MMP-2 同工型（Pro-MMP-2、活性 MMP-2、总 MMP-2）组织水平，并通过酶联免疫吸附试验（ELISA）分析了 MMP-14、TIMP-2 和总 MMP-2 的组织水平。作为对照，通过 ELISA 测量了 9 例接受冠状动脉旁路移植术的患者的 MMP-14 和 TIMP-2 主动脉组织水平，并通过明胶酶谱法测量了 11 例患者的 MMP-2 同工型。
结果
与对照组相比，aTAA 患者的活性 MMP-2 明显升高。aTAA 患者的 Pro-MMP-2 和 TIMP-2 水平明显降低。组间总 MMP-2 和 MMP-14 无显著差异。回归分析显示，TIMP-2 与 MMP-14/TIMP-2 比值以及 aTAA 中的活性 MMP-2 之间存在线性关系。通过分析 MMP-14 和 TIMP-2 在 ROC 分析中的作用可以忽略不计。
结论
与对照主动脉组织相比，aTAA 中 MMP-2 的激活量更大-这一因素似乎是动脉瘤形成的核心过程。当活性 MMP-2 相对于 Pro-MMP-2 超过 10%时，我们推断其源自动脉瘤组织，我们认为这是进一步研究 aTAA 生物标志物的起点。组织的 MMP-14/TIMP-2 比值可能作为决定因素调节 Pro-MMP-2 的激活程度，而 MMP-14 和 TIMP-2 的酶活性似乎在动脉瘤形成中不起关键作用。
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