HEPARIN INHIBITS THE INDUCTION OF 3 MATRIX METALLOPROTEINASES (STROMELYSIN, 92-KD GELATINASE, AND COLLAGENASE) IN PRIMATE ARTERIAL SMOOTH-MUSCLE CELLS
HEPARIN INHIBITS THE INDUCTION OF 3 MATRIX METALLOPROTEINASES (STROMELYSIN, 92-KD GELATINASE, AND COLLAGENASE) IN PRIMATE ARTERIAL SMOOTH-MUSCLE CELLS
复制标题
DOI：
10.1172/jci117191
复制
发表时间：
1994-05-01
影响因子：
15.9
通讯作者：
CLOWES, AW
中科院分区：
文献类型：
--
作者：
KENAGY, RD;NIKKARI, ST;CLOWES, AW
肝素抑制动脉平滑肌细胞的迁移和增殖，并改变细胞外基质。这些作用可能是肝素作用于降解基质的蛋白酶的结果。我们以前报道过肝素抑制组织型纤溶酶原激活物和间质胶原酶mRNA的诱导。我们已经研究了肝素影响基质金属蛋白酶家族其他成员的可能性。phobol酯增加了胶原酶、92-kD明胶酶和基质溶解素mRNA的表达水平，并增加了这些蛋白的合成。这些作用被肝素抑制，但不被其他糖胺聚糖，以剂量依赖的方式。staurosporine和phorbol酯预处理也抑制了这些基质金属蛋白酶的诱导，表明参与了蛋白激酶C途径。相反，72-kD明胶酶是组成性表达的，不受佛波酯和肝素的影响。金属蛋白酶组织抑制剂-1呈组构性表达，磷酯使其表达量略有增加。肝素对它没有影响。因此，肝素抑制四种蛋白酶（组织纤溶酶原激活剂、胶原酶、基质溶酶和92-kD明胶酶）的产生，这四种酶形成一个相互依赖的系统，能够降解细胞外基质的所有主要成分。
Heparin inhibits the migration and proliferation of arterial smooth muscle cells and modifies the extracellular matrix. These effects may be the result of heparin's effects on proteinases that degrade the matrix. We have previously reported that heparin inhibits the induction of tissue-type plasminogen activator and interstitial collagenase mRNA. We have investigated the possibility that heparin affects other members of the matrix metalloproteinase family. Phorbol ester increased the levels of mRNA of collagenase, 92-kD gelatinase and stromelysin as well as the synthesis of these proteins. These effects were inhibited by heparin, but not by other glycosaminoglycans, in a dose-dependent manner. The induction of these matrix metalloproteinases was also inhibited by staurosporine and pretreatment with phorbol ester indicating the involvement of the protein kinase C pathway. In contrast, the 72-kD gelatinase was expressed constitutively and was not affected by phorbol ester or heparin. Tissue inhibitor of metalloproteinases-1 was expressed constitutively and was slightly increased by phorbol ester. It was not affected by heparin. Thus, heparin inhibits the production of four proteinases (tissue plasminogen activator, collagenase, stromelysin and 92-kD gelatinase) that form an interdependent system capable of degrading all the major components of the extracellular matrix.