Pintucci Giuseppe, Yu Pey-Jen, Sharony Ram, Baumann F Gregory, Saponara Fiorella, Frasca Antonio, Galloway Aubrey C, Moscatelli David, Mignatti Paolo
The Seymour Cohn Cardiovascular Surgery Research Laboratory, New York University School of Medicine, New York, New York 10016, USA.
J Cell Biochem. 2003 Dec 1;90(5):1015-25. doi: 10.1002/jcb.10721.
Basic fibroblast growth factor (FGF-2) and matrix metalloproteinases (MMPs) play key roles in vascular remodeling. Because FGF-2 controls a number of proteolytic activities in various cell types, we tested its effect on vascular endothelial cell expression of MMP-3 (stromelysin-1), a broad-spectrum proteinase implicated in coronary atherosclerosis. Endothelial cells (EC) from FGF-2-/- mice are highly responsive to exogenous FGF-2 and were therefore used for this study. The results showed that treatment of microvascular EC with human recombinant FGF-2 results in strong induction of MMP-3 mRNA and protein expression. Upregulation of MMP-3 mRNA by FGF-2 requires de novo protein synthesis and activation of the ERK-1/2 pathway. FGF-2 concentrations (5-10 ng/ml) that induce rapid and prolonged (24 h) activation of ERK-1/2 upregulate MMP-3 expression. In contrast, lower concentrations (1-2 ng/ml) that induce robust but transient (<8 h) ERK-1/2 activation are ineffective. Inhibition of ERK-1/2 activation at different times (-0.5 h to +8 h) of EC treatment with effective FGF-2 concentrations blocks MMP-3 upregulation. Thus, FGF-2 induces EC expression of MMP-3 with a threshold dose effect that requires sustained activation of the ERK-1/2 pathway. Because FGF-2 controls other EC functions with a linear dose effect, these features indicate a unique role of MMP-3 in vascular remodeling.
碱性成纤维细胞生长因子（FGF-2）和基质金属蛋白酶（MMPs）在血管重塑中起关键作用。由于FGF-2控制多种细胞类型中的多种蛋白水解活性，我们测试了其对血管内皮细胞中MMP-3（基质溶解素-1）表达的影响，MMP-3是一种与冠状动脉粥样硬化有关的广谱蛋白酶。来自FGF-2基因敲除小鼠的内皮细胞（EC）对外源性FGF-2高度敏感，因此用于本研究。结果表明，用人重组FGF-2处理微血管EC可强烈诱导MMP-3 mRNA和蛋白表达。FGF-2对MMP-3 mRNA的上调需要从头合成蛋白质并激活ERK-1/2途径。诱导ERK-1/2快速且持续（24小时）激活的FGF-2浓度（5-10 ng/ml）上调MMP-3表达。相比之下，诱导强烈但短暂（<8小时）ERK-1/2激活的较低浓度（1-2 ng/ml）无效。在用有效FGF-2浓度处理EC的不同时间（-0.5小时至+8小时）抑制ERK-1/2激活可阻断MMP-3上调。因此，FGF-2以阈值剂量效应诱导EC表达MMP-3，这需要ERK-1/2途径的持续激活。由于FGF-2以线性剂量效应控制其他EC功能，这些特征表明MMP-3在血管重塑中具有独特作用。
