Plasminogen and matrix metalloproteinase activation by enzymatically modified low density lipoproteins in monocytes and smooth muscle cells
Plasminogen and matrix metalloproteinase activation by enzymatically modified low density lipoproteins in monocytes and smooth muscle cells
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DOI：
10.1160/th04-11-0720
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发表时间：
2005-04-01
影响因子：
6.7
通讯作者：
Klouche, M
中科院分区：
文献类型：
--
作者：
May, AE;Schmidt, R;Klouche, M
蛋白酶活性促进动脉粥样硬化斑块的进展和破裂。据描述，LDL 在血管壁内经过酶促修饰，产生致动脉粥样硬化部分 (E-LDL)。我们研究了 E-LDL 对单核细胞和血管平滑肌细胞 (VSMC) 中纤溶酶原和基质金属蛋白酶 (MMP) 激活的影响，以及细胞相互作用过程中 MMP 激活的影响。将人单核细胞、单核细胞 MonoMac6 细胞和人 VSMC 与人天然 LDL (n-LDL) 或 E-LDL 一起孵育 24 小时。与n-LDL相比，E-LDL诱导单核细胞中纤溶酶原激活系统以及MMP系统的大量激活，通过尿激酶受体（uPAR）、细胞外基质金属蛋白酶诱导物（EMMPRIN）和膜I型MMP（MTI-MMPMMP-14）的细胞表面表达增强以及活性uPA和MMP-9的分泌来测量。一致地，E-LDL处理的单核细胞表现出通过“基质胶”的迁移增加，这种迁移被MMP抑制剂加拉丁或纤溶酶抑制剂抑肽酶特异性消除。在VSMC中，E-LDL诱导MMP-1和MMP-2分泌。此外，单核细胞与 E-LDL 处理（而非 n-LDL 处理）VSMC 上清液一起孵育，可强烈诱导单核细胞中的 MMP-9，而阻断 mAb 抗 TNF-α 可抑制 MMP-9。 LDL 的酶促修饰可以直接激活单核细胞和 VSMC 中的 MMP 表达，并间接促进旁分泌、细胞因子介导的细胞间激活过程的诱导。因此，E-LDL 可能导致动脉粥样硬化进展、炎症和斑块破裂。
Protease activity promotes the progression and rupture of atherosclerotic plaques. LDL has been described to become enzymatically modified within the vessel wall yielding an atherogenic moiety (E-LDL). We studied the effect of E-LDL on the activation of plasminogen and matrix metal lop roteinases (MMPs) in monocytes and vascular smooth muscle cells (VSMCs) as well as on MMP activation during cellular interactions. Human monocytes, monocytic MonoMac6 cells and human VSMCs were incubated with human native LDL (n-LDL) or E-LDL for 24 hours. E-LDL in contrast to n-LDL induced substantial activation of the plasminogen activation system as well as of the MMP system in monocytic cells, as measured by enhanced cell surface expression of the urokinase receptor (uPAR),the extracellular matrix metalloproteinase Inducer (EMMPRIN) and the membrane type-I MMPs (MTI -MMPMMP-14),as well as by secretion of active uPA, and of MMP-9. Consistently, E-LDL-treated monocytes exhibited increased transmigration through "matrigel", which was specifically abrogated by the MMP inhibitor galardin or the plasmin inhibitor aprotinin. In VSMCs, E-LDL induced MMP-I and MMP-2 secretion. Moreover, monocyte incubation with supernatants of E-LDL-treated (but not n-LDL-treated)VSMCs strongly induced MMP-9 in monoytes, which was inhibited by blocking mAb anti-TNF-alpha. Together enzymatical modification of LDL allows a direct activation of MMP expression in monocytes and VSMCs, and indirectly promotes the induction of paracrine, cytokine-mediated intercellular activation processes. Thereby, E-LDL may contribute to atheroprogression, inflammation and plaque rupture.