1. Regulation of impaired angiogenesis in diabetic dermal wound healing by microRNA-26a.
- Author
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Icli B, Nabzdyk CS, Lujan-Hernandez J, Cahill M, Auster ME, Wara AK, Sun X, Ozdemir D, Giatsidis G, Orgill DP, and Feinberg MW
- Subjects
- Animals, Cell Movement, Cyclin-Dependent Kinase Inhibitor p27 genetics, Cyclin-Dependent Kinase Inhibitor p27 metabolism, Dermis drug effects, Dermis metabolism, Dermis pathology, Diabetes Mellitus, Experimental metabolism, Diabetes Mellitus, Experimental pathology, Endothelial Cells drug effects, Endothelial Cells metabolism, Endothelial Cells pathology, Fibroblasts metabolism, Fibroblasts pathology, Gene Expression Regulation, Glucose pharmacology, Humans, Inhibitor of Differentiation Protein 1 genetics, Inhibitor of Differentiation Protein 1 metabolism, Macrophages metabolism, Macrophages pathology, Male, Mast Cells metabolism, Mast Cells pathology, Mice, MicroRNAs antagonists & inhibitors, MicroRNAs metabolism, Neovascularization, Pathologic metabolism, Neovascularization, Pathologic pathology, Neovascularization, Pathologic therapy, Oligonucleotides, Antisense metabolism, Re-Epithelialization, Signal Transduction, Smad1 Protein metabolism, Vascular Endothelial Growth Factor A genetics, Vascular Endothelial Growth Factor A metabolism, Wounds, Nonpenetrating metabolism, Wounds, Nonpenetrating pathology, Wounds, Nonpenetrating therapy, Diabetes Mellitus, Experimental genetics, MicroRNAs genetics, Neovascularization, Pathologic genetics, Oligonucleotides, Antisense genetics, Smad1 Protein genetics, Wounds, Nonpenetrating genetics
- Abstract
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., (Copyright © 2016 Elsevier Ltd. All rights reserved.)
- Published
- 2016
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