Zoughaib Mohamed, Luong Duong, Garifullin Ruslan, Gatina Dilara Z, Fedosimova Svetlana V, Abdullin Timur I
Institute of Fundamental Medicine and Biology, Kazan Federal University, 420008 Kazan, Russia.
Institute of Fundamental Medicine and Biology, Kazan Federal University, 420008 Kazan, Russia; Institute of Materials Science and Nanotechnology, Bilkent University, 06800 Ankara, Turkey.
Mater Sci Eng C Mater Biol Appl. 2021 Jan;120:111660. doi: 10.1016/j.msec.2020.111660. Epub 2020 Oct 21.
Synthetic oligopeptides are a promising alternative to natural full-length growth factors and extracellular matrix (ECM) proteins in tissue regeneration and therapeutic angiogenesis applications. In this work, angiogenic properties of dual and triple compositions containing RGD, GHK peptides and copper (II) ions (Cu) were for the first time studied. To reveal specific in vitro effects of these compositions in three-dimensional scaffold, adamantyl group bearing peptides, namely Ada-Ahx-GGRGD (1) and Ada-Ahx-GGGHK (2), were effectively immobilized in bioinert pHEMA macroporous cryogel via host-guest β-cyclodextrin-adamantane interaction. The cryogels were additionally functionalized with Cu via the formation of GHK-Cu complex. Angiogenic responses of HUVECs grown within the cryogel ECM model were analyzed. The results demonstrate that the combination of RGD with GHK and further with Cu dramatically increases cell proliferation, differentiation, and production of a series of angiogenesis related cytokines and growth factors. Furthermore, the level of glutathione, a key cellular antioxidant and redox regulator, was altered in relation to the angiogenic effects. These results are of particular interest for establishing the role of multiple peptide signals on regeneration related processes and for developing improved tissue engineering materials.
在组织再生和治疗性血管生成应用中，合成寡肽是天然全长生长因子和细胞外基质（ECM）蛋白的一种有前景的替代物。在这项工作中，首次研究了含有RGD、GHK肽和铜（II）离子（Cu）的二元和三元组合物的血管生成特性。为了揭示这些组合物在三维支架中的特定体外效应，通过主客体β-环糊精-金刚烷相互作用，将带有金刚烷基团的肽，即Ada-Ahx-GGRGD（1）和Ada-Ahx-GGGHK（2）有效地固定在生物惰性的聚甲基丙烯酸羟乙酯大孔冷冻凝胶中。通过形成GHK-Cu络合物，冷冻凝胶还用Cu进行了额外的功能化。分析了在冷冻凝胶ECM模型中生长的人脐静脉内皮细胞（HUVECs）的血管生成反应。结果表明，RGD与GHK以及进一步与Cu的组合显著增加了细胞增殖、分化以及一系列血管生成相关细胞因子和生长因子的产生。此外，关键的细胞抗氧化剂和氧化还原调节剂谷胱甘肽的水平与血管生成效应相关而发生了改变。这些结果对于确定多种肽信号在再生相关过程中的作用以及开发改进的组织工程材料特别有意义。
