Sitagliptin-mediated preservation of endothelial progenitor cell function via augmenting autophagy enhances ischaemic angiogenesis in diabetes.
Sitagliptin-mediated preservation of endothelial progenitor cell function via augmenting autophagy enhances ischaemic angiogenesis in diabetes.
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西格列汀通过增强自噬介导的内皮祖细胞功能保存增强糖尿病缺血性血管生成
DOI：
10.1111/jcmm.13296
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发表时间：
2018-01
影响因子：
5.3
通讯作者：
Tan Y
中科院分区：
文献类型：
--
作者：
Dai X;Zeng J;Yan X;Lin Q;Wang K;Chen J;Shen F;Gu X;Wang Y;Chen J;Pan K;Cai L;Wintergerst KA;Tan Y
最近，二肽基肽酶-4（DPP-4）抑制剂西格列汀（一种主要的抗高血压药物）作为心血管疾病的治疗靶点，通过增加循环内皮祖细胞（EPC）的数量而受到广泛关注。然而，西格列汀对EPC功能的直接影响仍然难以捉摸。在这项研究中，我们评估了西格列汀对体内糖尿病后肢缺血（HLI）模型和体外EPC培养的促血管生成作用。在HLI手术后用西格列汀（捷诺维）治疗db/db小鼠有效地增强了缺血性血管生成和血液灌注，伴随着循环EPC数量的显著增加。用高糖处理正常小鼠骨髓来源的EPCs以模拟糖尿病高血糖。我们发现，高糖处理诱导EPC凋亡和管形成障碍，这是显着防止西格列汀预处理。一项机制研究发现，高糖处理EPCs可诱导氧化应激和细胞凋亡显著增加;西格列汀预处理EPCs可显著减弱高糖诱导的细胞凋亡、管形成障碍和氧化应激。此外，我们发现西格列汀通过激活AMP活化蛋白激酶/unc-51样自噬激活激酶1信号通路恢复了高糖损害的EPCs的基础自噬，尽管自噬抑制剂消除了西格列汀对EPCs的保护作用。总之，结果表明，西格列汀诱导的EPC血管生成功能的保护导致糖尿病缺血血管生成和血液灌注的改善，这很可能是通过西格列汀诱导的通过增强自噬预防EPC凋亡介导的。
Recently, the dipeptidyl peptidase‐4 (DPP‐4) inhibitor sitagliptin, a major anti‐hyperglycaemic agent, has received substantial attention as a therapeutic target for cardiovascular diseases via enhancing the number of circulating endothelial progenitor cells (EPCs). However, the direct effects of sitagliptin on EPC function remain elusive. In this study, we evaluated the proangiogenic effects of sitagliptin on a diabetic hind limb ischaemia (HLI) model in vivo and on EPC culture in vitro. Treatment of db/db mice with sitagliptin (Januvia) after HLI surgery efficiently enhanced ischaemic angiogenesis and blood perfusion, which was accompanied by significant increases in circulating EPC numbers. EPCs derived from the bone marrow of normal mice were treated with high glucose to mimic diabetic hyperglycaemia. We found that high glucose treatment induced EPC apoptosis and tube formation impairment, which were significantly prevented by sitagliptin pretreatment. A mechanistic study found that high glucose treatment of EPCs induced dramatic increases in oxidative stress and apoptosis; pretreatment of EPCs with sitagliptin significantly attenuated high glucose‐induced apoptosis, tube formation impairment and oxidative stress. Furthermore, we found that sitagliptin restored the basal autophagy of EPCs that was impaired by high glucose via activating the AMP‐activated protein kinase/unc‐51‐like autophagy activating kinase 1 signalling pathway, although an autophagy inhibitor abolished the protective effects of sitagliptin on EPCs. Altogether, the results indicate that sitagliptin‐induced preservation of EPC angiogenic function results in an improvement of diabetic ischaemia angiogenesis and blood perfusion, which are most likely mediated by sitagliptin‐induced prevention of EPC apoptosis via augmenting autophagy.
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影响因子：
7.7
作者：
He C;Zhu H;Li H;Zou MH;Xie Z
通讯作者：
Xie Z
影响因子：
56.9
作者：
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通讯作者：
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影响因子：
9.3
作者：
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通讯作者：
Miura T