Hanemaaijer R, Koolwijk P, le Clercq L, de Vree W J, van Hinsbergh V W
Gaubius Laboratory IVVO-TNO, Leiden, The Netherlands.
Biochem J. 1993 Dec 15;296 ( Pt 3)(Pt 3):803-9. doi: 10.1042/bj2960803.
Matrix metalloproteinases (MMPs) play a role in tissue remodelling and angiogenesis. We have investigated the expression and regulation of MMP-1 (interstitial collagenase), MMP-2 (gelatinase A), MMP-3 (stromelysin 1), MMP-7 (matrilysin), MMP-9 (gelatinase B) and their inhibitors TIMP-1 and TIMP-2 in human umbilical vein, femoral vein and microvascular endothelial cells, and compared these data with those obtained with human synovial fibroblasts. Non-stimulated vein endothelial cells expressed the mRNAs for MMP-1, MMP-2, TIMP-1 and TIMP-2. MMP-3 mRNA and protein were undetectable or only weakly expressed, but could be stimulated by the inflammatory mediator tumour necrosis factor alpha (TNF alpha). The expression of MMP-3 and MMP-1 was further enhanced by phorbol 12-myristate 13-acetate (PMA). Phorbol ester also induced TIMP-1 and MMP-9, the expression of the latter being further enhanced by TNF alpha or interleukin 1 alpha (IL-1 alpha). Similar stimulatory effects were observed in microvascular endothelial cells. Hence the inflammatory mediator TNF alpha induces/enhances the production of several matrix metalloproteinases in human endothelial cells. On the other hand, MMP-2 and TIMP-2 were not affected or were affected in a variable way by TNF alpha and/or phorbol ester, suggesting a dissimilar regulation of these proteins. The cyclic AMP-enhancing agent forskolin affected the production of MMPs in a cell-type-specific way. In human vein endothelial cells it enhanced the PMA-mediated induction of MMP-9, whereas it suppressed this induction in human microvascular endothelial cells and in synovial fibroblasts. On the other hand, forskolin suppressed the PMA-mediated induction of MMP-1 and MMP-3 in synovial fibroblasts, while it enhanced or did not affect this induction in various types of human endothelial cells. These observations may have implications for future pharmacological intervention in angiogenesis.
基质金属蛋白酶（MMPs）在组织重塑和血管生成中发挥作用。我们研究了MMP-1（间质胶原酶）、MMP-2（明胶酶A）、MMP-3（基质溶解素1）、MMP-7（基质溶素）、MMP-9（明胶酶B）及其抑制剂TIMP-1和TIMP-2在人脐静脉、股静脉和微血管内皮细胞中的表达及调控，并将这些数据与用人滑膜成纤维细胞获得的数据进行比较。未受刺激的静脉内皮细胞表达MMP-1、MMP-2、TIMP-1和TIMP-2的mRNA。MMP-3的mRNA和蛋白检测不到或仅微弱表达，但可被炎症介质肿瘤坏死因子α（TNFα）刺激。佛波酯12-肉豆蔻酸酯13-乙酸酯（PMA）进一步增强了MMP-3和MMP-1的表达。佛波酯还诱导TIMP-1和MMP-9，TNFα或白细胞介素1α（IL-1α）可进一步增强后者的表达。在微血管内皮细胞中观察到类似的刺激作用。因此，炎症介质TNFα诱导/增强人内皮细胞中几种基质金属蛋白酶的产生。另一方面，MMP-2和TIMP-2不受TNFα和/或佛波酯的影响或以可变方式受到影响，表明这些蛋白的调控不同。环磷酸腺苷增强剂福斯高林以细胞类型特异性方式影响MMPs的产生。在人静脉内皮细胞中，它增强了PMA介导的MMP-9诱导，而在人微血管内皮细胞和滑膜成纤维细胞中则抑制了这种诱导。另一方面，福斯高林抑制滑膜成纤维细胞中PMA介导的MMP-1和MMP-3诱导，而在各种类型的人内皮细胞中它增强或不影响这种诱导。这些观察结果可能对未来血管生成的药物干预有影响。
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