Chang Jin-Hong, Javier Joel A D, Chang Gene-Yuan, Oliveira Hailton B, Azar Dimitri T
Corneal, External Disease and Refractive Surgery Service, Massachusetts Eye and Ear Infirmary and the Schepens Eye Research Institute, Harvard Medical School, 243 Charles Street, Boston, MA 02114, United States.
FEBS Lett. 2005 Jul 4;579(17):3601-6. doi: 10.1016/j.febslet.2005.05.043.
Several anti-angiogenic factors are derived from proteolytic processing of large molecules including endostatin from type XVIII collagen and angiostatin from plasminogen. In previous studies we showed that neostatin-7, the C-terminal 28kDa endostatin-spanning proteolytic fragment, is generated from the proteolytic action of matrix metalloproteinase matrilysin (MMP)-7 on type XVIII collagen. Now, we report a second member of the neostatin family of proteins, neostatin-14. Given the small quantities of neostatin-7 and -14 generated by the breakdown of naturally occurring collagen XVIII (using MMP-7 and -14, respectively), we used two other approaches to characterize the anti-angiogenic properties of these molecules: murine recombinant neostatin in vitro, and gene therapy. We demonstrate that murine recombinant neostatin-7 inhibits calf pulmonary artery endothelial cell proliferation and that microinjection of neostatin-7 and neostatin-14 naked DNA into the corneal stroma of mice results in significant reduction of basic fibroblast growth factor-induced corneal neovascularization. These results provide supportive evidence of the possible anti-angiogenic effect of neostatins.
几种抗血管生成因子来源于大分子的蛋白水解加工，包括来自 XVIII 型胶原蛋白的内皮抑素和来自纤溶酶原的血管抑素。在先前的研究中，我们表明新抑素 -7，即 C 末端 28kDa 的跨越内皮抑素的蛋白水解片段，是由基质金属蛋白酶基质溶素（MMP）-7 对 XVIII 型胶原蛋白的蛋白水解作用产生的。现在，我们报道了新抑素家族蛋白的第二个成员，新抑素 -14。鉴于天然存在的 XVIII 型胶原蛋白分解产生的新抑素 -7 和 -14 量很少（分别使用 MMP -7 和 -14），我们采用了另外两种方法来表征这些分子的抗血管生成特性：体外小鼠重组新抑素和基因治疗。我们证明小鼠重组新抑素 -7 抑制小牛肺动脉内皮细胞增殖，并且将新抑素 -7 和新抑素 -14 的裸 DNA 显微注射到小鼠角膜基质中可显著减少碱性成纤维细胞生长因子诱导的角膜新生血管形成。这些结果为新抑素可能的抗血管生成作用提供了支持性证据。
