DPP-4 inhibitors promote proliferation and migration of rat brain microvascular endothelial cells under hypoxic/high-glucose conditions, potentially through the SIRT1/HIF-1/VEGF pathway
DPP-4 inhibitors promote proliferation and migration of rat brain microvascular endothelial cells under hypoxic/high-glucose conditions, potentially through the SIRT1/HIF-1/VEGF pathway
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DOI：
10.1111/cns.13042
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发表时间：
2019-03-01
影响因子：
5.5
通讯作者：
Liu, Li-Ping
中科院分区：
文献类型：
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作者：
Mi, Dong-Hua;Fang, Hong-Juan;Liu, Li-Ping
糖尿病中的血管疾病，例如中风，是一个重大的公共卫生负担。近年来，二肽基肽酶4 （DPP-4）抑制剂利格列汀被发现可以对抗糖尿病患者的脑卒中，在药物重新定位和适应症扩展方面显示出巨大的前景。然而，这种保护机制的分子基础尚不清楚。方法采用免疫荧光染色和Western blotting检测DPP-4在大鼠脑微血管内皮细胞（rBMVECs）中的表达和定位。采用MTT法和transwell法分别测定DPP-4抑制剂对rbmves细胞增殖和迁移的影响。DPP-4抑制对VEGF、eNOS、HIF-1 α等分子标志物表达的影响分别用qRT-PCR和Western blotting检测SIRT1 mRNA和蛋白水平。结果DPP-4抑制剂（40 nmol/L利格列汀、30 mu mol/L小檗碱）对缺氧/高糖诱导的rbmvec增殖和迁移损伤具有保护作用。DPP-4抑制剂可以抵消低氧/高糖条件对VEGF、eNOS、HIF-1 α和SIRT1表达的减弱作用，而用1 mmol/L烟酰胺抑制SIRT1可以完全消除这种减弱作用。结论DPP-4抑制剂对rBMVECs缺氧/高糖损伤的保护作用可能通过SIRT1/HIF-1 α /VEGF通路介导。
Background Vascular disease in diabetes, for example, stroke, presents a significant public health burden. Recently, the dipeptidyl peptidase 4 (DPP-4) inhibitor linagliptin has been found to counteract stroke among diabetic patients, showing great promise in drug repurposing and indication expansion. However, the molecular basis of this protection mechanism remains unknown. Methods The expression and localization of DPP-4 in rat brain microvascular endothelial cells (rBMVECs) were assessed with immunofluorescent staining and Western blotting. The effects of DPP-4 inhibitors on cell proliferation and migration of rBMVECs were determined using MTT and transwell assays, separately. The influence of DPP-4 inhibition on the expression of molecular markers (eg, VEGF, eNOS, HIF-1 alpha. SIRT1) was examined at both mRNA and protein levels with qRT-PCR and Western blotting, individually. Results DPP-4 inhibitors (40 nmol/L linagliptin, 30 mu mol/L berberine) offer protection from hypoxia/high glucose induced impairments in the proliferation and migration of rBMVECs. Treatment with DPP-4 inhibitors counteracted the attenuating effects of hypoxic/high-glucose conditions on the expression of VEGF, eNOS, HIF-1 alpha, and SIRT1, which can be completely eliminated by the inhibition of SIRT1 with 1 mmol/L nicotinamide. Conclusions The protection of rBMVECs from hypoxia/high-glucose induced impairment by DPP-4 inhibitors may be mediated by the SIRT1/HIF-1 alpha/VEGF pathway.