Regulation of impaired angiogenesis in diabetic dermal wound healing by microRNA-26a.
Regulation of impaired angiogenesis in diabetic dermal wound healing by microRNA-26a.
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DOI：
10.1016/j.yjmcc.2016.01.007
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发表时间：
2016-02
影响因子：
5
通讯作者：
Feinberg MW
中科院分区：
文献类型：
--
作者：
Icli B;Nabzdyk CS;Lujan-Hernandez J;Cahill M;Auster ME;Wara AK;Sun X;Ozdemir D;Giatsidis G;Orgill DP;Feinberg MW
伤口愈合是对损伤的生理修复反应，是一个精心安排的过程，包括止血、细胞迁移、增殖、血管生成、细胞外基质沉积、伤口收缩和再上皮化。然而，2型糖尿病（T2D）患者经常受到伤口愈合受损的困扰，并发展为慢性伤口或糖尿病性溃疡，并可能导致包括截肢在内的并发症。在此，我们研究了microRNA-26a （miR-26a）在糖尿病伤口愈合模型中的潜在作用。内皮细胞（ECs）对高葡萄糖的反应会迅速诱导miR-26a的表达。与WT小鼠相比，损伤后4天，db/db小鼠的穿孔皮肤活检损伤显示miR-26a的表达增加（约3.5倍）。在db/db小鼠中，局部给药miR-26a抑制剂LNA-anti-miR-26a诱导血管生成（高达80%），肉芽组织厚度增加（2.5倍），并加速伤口愈合（9天后53%）。这些影响与M1/M2巨噬细胞比例的改变无关。在机制上，抑制miR-26a在糖尿病小鼠损伤后9天的ECs中增加了其靶基因SMAD1。此外，高糖降低了SMAD1-3 ' -UTR的活性。用na -anti- mir -26a处理的糖尿病皮肤创面增加了下游调节剂ID1或SMAD1的表达，降低了细胞周期抑制剂p27的表达。这些发现证实miR-26a通过特异性调节损伤后血管生成反应，在糖尿病小鼠皮肤创伤进展中发挥重要调节作用，并证明miR-26a的中和可能作为一种新的治疗方法。
Wound healing is a physiological reparative response to injury and a well-orchestrated process that involves hemostasis, cellular migration, proliferation, angiogenesis, extracellular matrix deposition, and wound contraction and re-epithelialization. However, patients with type 2 diabetes mellitus (T2D) are frequently afflicted with impaired wound healing that progresses into chronic wounds or diabetic ulcers, and may lead to complications including limb amputation. Herein, we investigate the potential role of microRNA-26a (miR-26a) in a diabetic model of wound healing. Expression of miR-26a is rapidly induced in response to high glucose in endothelial cells (ECs). Punch skin biopsy wounding of db/db mice revealed increased expression of miR-26a (~3.5-fold) four days post-wounding compared to that of WT mice. Local administration of a miR-26a inhibitor, LNA-anti-miR-26a, induced angiogenesis (up to ~80%), increased granulation tissue thickness (by 2.5-fold) and accelerated wound closure (53% after nine days) compared to scrambled anti-miR controls in db/db mice. These effects were independent of altered M1/M2 macrophage ratios. Mechanistically, inhibition of miR-26a increased its target gene SMAD1 in ECs nine days post-wounding of diabetic mice. In addition, high glucose reduced activity of the SMAD1-3’-UTR. Diabetic dermal wounds treated with LNA-anti-miR-26a had increased expression of ID1, a downstream modulator or SMAD1, and decreased expression of the cell cycle inhibitor p27. These findings establish miR-26a as an important regulator on the progression of skin wounds of diabetic mice by specifically regulating the angiogenic response after injury, and demonstrate that neutralization of miR-26a may serve as a novel approach for therapy.