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Topical prolyl hydroxylase domain-2 silencing improves diabetic murine wound closure

Wetterau M; George F; Weinstein A; Nguyen PD; Tutela JP; Knobel D; Cohen Ba O; Warren SM; Saadeh PB
Prolyl hydroxylase domain 2 (PHD2) has been implicated in several pathways of cell signaling, most notably in its regulation of hypoxia-inducible factor (HIF)-1alpha stability. In normoxia, PHD2 hydroxylates proline residues on HIF-1alpha, rendering it inactive. However, in hypoxia, PHD2 is inactive, HIF-1alpha is stabilized and downstream effectors such as vascular endothelial growth factor and fibroblast growth factor-2 are produced to promote angiogenesis. In the present study we utilize RNA interference to PHD2 to promote therapeutic angiogenesis in a diabetic wound model, presumably by the stabilization of HIF-1alpha. Stented wounds were created on the dorsum of diabetic Lepr db/db mice. Mice were treated with PHD2 small interfering RNA (siRNA) or nonsense siRNA. Wounds were measured photometrically on days 0-28. Wounds were harvested for histology, protein, and RNA analysis. Diabetic wounds treated with siRNA closed within 21+/-1.2 days; sham-treated closed in 28+/-1.5 days. By day 7, Western blot revealed near complete suppression of PHD protein and corresponding increased HIF-1alpha. Angiogenic mediators vascular endothelial growth factor and fibroblast growth factor-2 were elevated, corresponding to increased CD31 staining in the treated groups. siRNA-mediated silencing of PHD2 increases HIF-1alpha and several mediators of angiogenesis. This corresponded to improved time to closure in diabetic wounds compared with sham-treated wounds. These findings suggest that impaired wound healing in diabetes can be ameliorated with therapeutic angiogenesis
PMCID:3200292
PMID: 21627711
ISSN: 1524-475x
CID: 134339