Nguyen Ngoc-Quynh-Nhu, Tabruyn Sebastien P, Lins Laurence, Lion Michelle, Cornet Anne M, Lair Florence, Rentier-Delrue Francoise, Brasseur Robert, Martial Joseph A, Struman Ingrid
Laboratory of Molecular Biology and Genetic Engineering, Center of Biomedical Integrative Genoproteomics, University of Liège, B-4000 Liège, Belgium.
Proc Natl Acad Sci U S A. 2006 Sep 26;103(39):14319-24. doi: 10.1073/pnas.0606638103. Epub 2006 Sep 14.
Angiogenesis is a crucial step in many pathologies, including tumor growth and metastasis. Here, we show that tilted peptides exert antiangiogenic activity. Tilted (or oblique-oriented) peptides are short peptides known to destabilize membranes and lipid cores and characterized by an asymmetric distribution of hydrophobic residues along the axis when helical. We have previously shown that 16-kDa fragments of the human prolactin/growth hormone (PRL/GH) family members are potent angiogenesis inhibitors. Here, we demonstrate that all these fragments possess a 14-aa sequence having the characteristics of a tilted peptide. The tilted peptides of human prolactin and human growth hormone induce endothelial cell apoptosis, inhibit endothelial cell proliferation, and inhibit capillary formation both in vitro and in vivo. These antiangiogenic effects are abolished when the peptides' hydrophobicity gradient is altered by mutation. We further demonstrate that the well known tilted peptides of simian immunodeficiency virus gp32 and Alzheimer's beta-amyloid peptide are also angiogenesis inhibitors. Taken together, these results point to a potential new role for tilted peptides in regulating angiogenesis.
血管生成是包括肿瘤生长和转移在内的许多病理过程中的关键步骤。在此，我们表明倾斜肽具有抗血管生成活性。倾斜（或倾斜取向）肽是已知会破坏膜和脂质核心稳定性的短肽，其特征在于螺旋时疏水残基沿轴的不对称分布。我们之前已经表明，人类催乳素/生长激素（PRL/GH）家族成员的16 kDa片段是有效的血管生成抑制剂。在此，我们证明所有这些片段都具有一段具有倾斜肽特征的14个氨基酸的序列。人类催乳素和人类生长激素的倾斜肽在体外和体内均可诱导内皮细胞凋亡、抑制内皮细胞增殖并抑制毛细血管形成。当通过突变改变肽的疏水性梯度时，这些抗血管生成作用就会消失。我们进一步证明，猿猴免疫缺陷病毒gp32和阿尔茨海默病β-淀粉样肽的著名倾斜肽也是血管生成抑制剂。综上所述，这些结果表明倾斜肽在调节血管生成方面可能具有新的作用。
