Deininger Martin H, Wybranietz Wolfgang A, Graepler Florian T C, Lauer Ulrich M, Meyermann Richard, Schluesener Hermann J
Institute of Brain Research, University of Tuebingen Medical School, Calwer Str. 3, D-72076 Tuebingen, Germany.
FASEB J. 2003 Jul;17(10):1267-76. doi: 10.1096/fj.02-1118com.
Endostatin is a 20 kDa carboxyl-terminal fragment of collagen XVIII that, when added exogenously, inhibits endothelial proliferation and migration in vitro and angiogenesis and tumor growth in vivo. Previous results showed endostatin/collagen XVIII labeling in few endothelial cells in human glioblastoma multiforme. We have now observed constitutive release of endostatin from one of four endothelial cell lines. Induction of endostatin release was observed after H2O2, an in vitro model of cell stress, CoCl2, a model of hypoxia, and by IFN-gamma challenge. Endostatin expression and release was reduced by the nitric oxide synthase inhibitors aminoguanidine and L-NAME and induced by the NO synthase-independent NO donors sodium nitroprusside (SNP) and spermine-NONO-ate. SNP-mediated endostatin induction was abrogated by the soluble guanylate cyclase inhibitor 1H-(1.2.4) oxadiazolo (4,3-A) quinoxalin-1-one. Adenoviral endostatin transduction resulted in the release of endostatin from endothelial cells and in down-regulation of iNOS (NOS2) and eNOS (NOS3), and surprisingly in a 10% induction of PCNA. These results describe the modulation of endostatin release by the NO signaling cascade and provide important new pharmacological information for the systemic induction of endogenous endostatin release by common NO donor pharmacotherapy.
内皮抑素是胶原蛋白 XVIII 的一个 20 kDa 的羧基末端片段，外源性添加时，它在体外可抑制内皮细胞增殖和迁移，在体内可抑制血管生成和肿瘤生长。先前的结果显示，在多形性胶质母细胞瘤的少数内皮细胞中有内皮抑素/胶原蛋白 XVIII 标记。我们现在观察到四种内皮细胞系之一可组成性释放内皮抑素。在 H2O2（一种细胞应激的体外模型）、CoCl2（一种缺氧模型）处理后以及经 IFN-γ 刺激后，可观察到内皮抑素释放的诱导。一氧化氮合酶抑制剂氨基胍和 L-NAME 可降低内皮抑素的表达和释放，而一氧化氮合酶非依赖性一氧化氮供体硝普钠（SNP）和精胺 - NONO - 酸盐可诱导其表达和释放。可溶性鸟苷酸环化酶抑制剂 1H-(1.2.4)恶二唑并(4,3 - A)喹喔啉 - 1 - 酮可消除 SNP 介导的内皮抑素诱导。腺病毒介导的内皮抑素转导导致内皮细胞释放内皮抑素，并下调诱导型一氧化氮合酶（NOS2）和内皮型一氧化氮合酶（NOS3），令人惊讶的是，还可使增殖细胞核抗原（PCNA）诱导增加 10%。这些结果描述了一氧化氮信号级联对内皮抑素释放的调节作用，并为通过常见的一氧化氮供体药物疗法全身诱导内源性内皮抑素释放提供了重要的新药理学信息。
