Davis Heart & Lung Research Institute, The Ohio State University College of Medicine, Columbus, OH, USA.
Vascul Pharmacol. 2011 Jul-Sep;55(1-3):2-9. doi: 10.1016/j.vph.2011.03.001. Epub 2011 Mar 10.
Evidence from both clinical and experimental studies indicates that Di-peptidyl peptidase-IV (DPP-4) inhibition may mediate favorable effects on the cardiovascular system. The objective of this study was to examine the acute effects of DPP-4 inhibition on vascular responses and to study the underlying mechanisms of alteration in tone. Aortic segments from C57BL/6 mice were treated with vasoconstrictors and exposed to various doses of alogliptin, a selective DPP-4 inhibitor. Vasodilator responses were evaluated using pathway specific antagonists to elucidate mechanisms of response. In parallel experiments, cultured human umbilical vein endothelial cells (HUVEC) were exposed to varying concentrations of alogliptin to evaluate the effects on candidate vasodilator pathways. Alogliptin relaxed phenylephrine and U46619 pre-constricted aortic segments in a dose dependent manner. Relaxation responses were not affected by the glucagon-like peptide-1 (GLP-1) receptor antagonist, exendin fragment 9-39 (88 ± 6 vs. 91 ± 2, p < 0.001). Vascular relaxation to alogliptin was significantly decreased by endothelial denudation, L-N(G)-monomethyl-arginine citrate (L-NMMA) and by the soluble guanylate cyclase inhibitor ODQ. DPP-4 inhibition induced relaxation was completely abolished by a combination of L-NMMA, charybdotoxin and apamin. Incubation of HUVECs with alogliptin resulted in eNOS and Akt phosphorylation (Ser(1177) and Ser(473) respectively) paralleled by a rapid increase in nitric oxide. Inhibition of Src kinase decreased eNOS and Akt phosphorylation, in contrast to a lack of any effect on insulin mediated activation of the eNOS-Akt, suggesting that alogliptin mediates vasodilation through Src kinase mediated effects on eNOS-Akt. DPP-4 inhibition by alogliptin mediates rapid vascular relaxation via GLP-1 independent, Src-Akt-eNOS mediated NO release and the activation of vascular potassium channels.
临床和实验研究都表明二肽基肽酶-4（DPP-4）抑制剂可能对心血管系统产生有益影响。本研究的目的是观察 DPP-4 抑制对血管反应的急性影响，并研究其对张力变化的潜在机制。用血管收缩剂处理 C57BL/6 小鼠的主动脉段，并暴露于不同剂量的阿格列汀（一种选择性 DPP-4 抑制剂）。使用特定途径的拮抗剂评估血管舒张反应，以阐明反应机制。在平行实验中，将培养的人脐静脉内皮细胞（HUVEC）暴露于不同浓度的阿格列汀，以评估对候选血管舒张途径的影响。阿格列汀以剂量依赖性方式松弛预先用苯肾上腺素和 U46619 收缩的主动脉段。血管舒张反应不受胰高血糖素样肽-1（GLP-1）受体拮抗剂 exendin 片段 9-39 的影响（88 ± 6 对 91 ± 2，p < 0.001）。内皮剥脱、L-N(G)-单甲基精氨酸柠檬酸盐（L-NMMA）和可溶性鸟苷酸环化酶抑制剂 ODQ 显著降低阿格列汀引起的血管舒张。L-NMMA、霍乱毒素和阿帕米联合使用完全消除了 DPP-4 抑制诱导的舒张作用。阿格列汀孵育 HUVEC 导致内皮型一氧化氮合酶（eNOS）和 Akt 磷酸化（分别为 Ser(1177)和 Ser(473)），同时一氧化氮迅速增加。Src 激酶抑制剂降低了 eNOS 和 Akt 的磷酸化，而对胰岛素介导的 eNOS-Akt 激活没有任何影响，这表明阿格列汀通过 Src 激酶介导的 eNOS-Akt 作用介导血管舒张。阿格列汀通过 DPP-4 抑制介导快速血管舒张，途径为 GLP-1 非依赖性、Src-Akt-eNOS 介导的一氧化氮释放和血管钾通道的激活。
