Modulation of miR29a improves impaired post-ischemic angiogenesis in hyperglycemia
Modulation of miR29a improves impaired post-ischemic angiogenesis in hyperglycemia
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DOI：
10.1177/1535370217716424
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发表时间：
2017-08-01
影响因子：
3.2
通讯作者：
Dokun, Ayotunde O.
中科院分区：
文献类型：
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作者：
Chen, Lingdan;Okeke, Emmanuel;Dokun, Ayotunde O.
糖尿病患者血管生成受损，这导致外周动脉疾病结局较差。在实验性外周动脉疾病中，糖尿病小鼠的血管生成和灌注恢复受损。我们最近发现，去整合素和金属蛋白酶结构域蛋白12（ADAM 12）在缺血性内皮细胞中上调，并在实验性外周动脉疾病后缺血后血管生成和灌注恢复中发挥关键作用。在这里，我们研究了miR29a在缺血内皮细胞ADAM 12表达调节中的作用，以及高血糖如何对这种调节产生负面影响。我们还探索了调节miR29 a是否可以改善与高血糖症相关的缺血后血管生成受损。此外，我们测试了在血管内皮生长因子信号传导受损的情况下，miR29a调节是否可以改善缺血后血管生成。我们在缺血内皮细胞中强制miR29a表达并评估ADAM 12表达。我们还评估了体内和体外高血糖是否损害缺血诱导的ADAM12上调和miR29a下调。最后，我们确定在缺血和高血糖中调节内皮细胞miR29a表达是否可以改善受损的内皮细胞功能。我们发现在缺血条件下，血管内皮细胞中的ADAM 12上调，miR 29 a下调。miR29a在缺血内皮细胞中的强制表达阻止了ADAM12的上调。在1型糖尿病小鼠的缺血后肢和暴露于模拟缺血加高血糖的内皮细胞中，ADAM12上调和miR29a下调减弱，而血管生成受损。用miR29a抑制剂敲低miR29a足以改善模拟缺血加高血糖中的ADAM12上调和血管生成。它也足以改善1型糖尿病小鼠体内的灌注恢复和体外血管生成，即使血管内皮生长因子信号转导被阻断抗体破坏。总之，MiR29a在缺血中调节内皮细胞ADAM12上调，并且这在高血糖中受损。调节miR29a改善与高血糖症相关的缺血后血管生成受损。
Individuals with diabetes mellitus suffer from impaired angiogenesis and this contributes to poorer peripheral arterial disease outcomes. In experimental peripheral arterial disease, angiogenesis and perfusion recovery are impaired in mice with diabetes. We recently showed that a disintegrin and metalloproteinase domain-containing protein 12 (ADAM12) is upregulated in ischemic endothelial cells and plays a key role in post-ischemic angiogenesis and perfusion recovery following experimental peripheral arterial disease. Here we investigated the role of miR29a in the regulation of endothelial cell ADAM12 expression in ischemia and how hyperglycemia negatively affects this regulation. We also explored whether modulating miR29a can improve impaired post-ischemic angiogenesis associated with hyperglycemia. Additionally, we tested whether miR29a modulation could improve post ischemic angiogenesis in the setting of impaired vascular endothelial growth factor signaling. We forced miR29a expression in ischemic endothelial cells and assessed ADAM12 expression. We also evaluated whether hyperglycemia invivo and invitro impair ischemia-induced ADAM12 upregulation and miR29a downregulation. Lastly, we determined whether modulating endothelial cell miR29a expression in ischemia and hyperglycemia could improve impaired endothelial cell functions. We found under ischemic conditions where ADAM12 is upregulated in endothelial cells, miR29a is downregulated. Forced expression of miR29a in ischemic endothelial cell prevented ADAM12 upregulation. In ischemic hind limbs of mice with type 1 diabetes and in endothelial cells exposed to simulated ischemia plus hyperglycemia, ADAM12 upregulation and miR29a downregulation were blunted while angiogenesis was impaired. Knocking down miR29a with an miR29a inhibitor was sufficient to improve ADAM12 upregulation and angiogenesis in simulated ischemia plus hyperglycemia. It was also sufficient to improve perfusion recovery in type 1 diabetes mellitus mice invivo and angiogenesis invitro even when vascular endothelial growth factor signaling was impaired with blocking antibodies. In conclusion, MiR29a regulates endothelial cell ADAM12 upregulation in ischemia and this is impaired in hyperglycemia. Modulating miR29a improves impaired post-ischemic angiogenesis associated with hyperglycemia.