Remm Friederike, Kränkel Nicolle, Lener Daniela, Drucker Daniel J, Sopper Sieghart, Brenner Christoph
Department of Internal Medicine III, Cardiology and Angiology, Medical University of Innsbruck, Innsbruck, Austria.
Department of Cardiology, Charité-Universitätsmedizin Berlin, Campus Benjamin Franklin, Berlin, Germany.
Stem Cells Int. 2018 Feb 8;2018:5284963. doi: 10.1155/2018/5284963. eCollection 2018.
DPP4 inhibitors (gliptins) are commonly used antidiabetic drugs for the treatment of type 2 diabetes. Gliptins also act in a glucose-independent manner and show vasoregenerative effects. We have shown that gliptins can remarkably accelerate vascular healing after vascular injury. However, the underlying mechanisms remain unclear. Here, we examined potential signaling pathways linking gliptins to enhanced endothelial regeneration.
We used wild-type and GLP1 receptor knockout () mice to investigate the underlying mechanisms of gliptin-induced reendothelialization. The prototype DPP4 inhibitor sitagliptin accelerated endothelial healing in both animal models. Improved endothelial growth was associated with gliptin-mediated progenitor cell recruitment into the diseased vascular wall via the SDF1-CXCR4 axis independent of GLP1R-dependent signaling pathways. Furthermore, SDF1 showed direct proproliferative effects on endothelial cells. Excessive neointimal formation was not observed in gliptin- or placebo-treated mice.
We identified the SDF1-CXCR4 axis as a crucial signaling pathway for endothelial regeneration after acute vascular injury. Furthermore, SDF1 can directly increase endothelial cell proliferation. Gliptin-mediated potentiation of endothelial regeneration was preserved in animals. Thus, gliptin-mediated endothelial regeneration proceeds through SDF-1/CXCR4 in a GLP1R-independent manner after acute vascular injury.
二肽基肽酶4抑制剂（格列汀类）是治疗2型糖尿病常用的抗糖尿病药物。格列汀类还以不依赖葡萄糖的方式发挥作用，并显示出血管再生作用。我们已经表明，格列汀类可显著加速血管损伤后的血管愈合。然而，其潜在机制仍不清楚。在此，我们研究了将格列汀类与增强的内皮再生联系起来的潜在信号通路。
我们使用野生型和胰高血糖素样肽1受体敲除（）小鼠来研究格列汀类诱导再内皮化的潜在机制。原型二肽基肽酶4抑制剂西他列汀在两种动物模型中均加速了内皮愈合。内皮生长的改善与格列汀类通过SDF1-CXCR4轴介导祖细胞募集到病变血管壁中有关，该过程独立于依赖胰高血糖素样肽1受体的信号通路。此外，SDF1对内皮细胞显示出直接的促增殖作用。在接受格列汀类或安慰剂治疗的小鼠中未观察到过度的内膜增生。
我们确定SDF1-CXCR4轴是急性血管损伤后内皮再生的关键信号通路。此外，SDF1可直接增加内皮细胞增殖。格列汀类介导的内皮再生增强在动物中得以保留。因此，急性血管损伤后，格列汀类介导的内皮再生通过SDF-1/CXCR4以不依赖胰高血糖素样肽1受体 的方式进行。
