| Topical prolyl hydroxylase domain-2 silencing improves diabetic murine wound closure. | |
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MedLine Citation:
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PMID: 21627711 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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Prolyl hydroxylase domain 2 (PHD2) has been implicated in several pathways of cell signaling, most notably in its regulation of hypoxia-inducible factor (HIF)-1α stability. In normoxia, PHD2 hydroxylates proline residues on HIF-1α, rendering it inactive. However, in hypoxia, PHD2 is inactive, HIF-1α 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-1α. 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-1α. 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-1α 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. |
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Authors:
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Meredith Wetterau; Finny George; Andrew Weinstein; Phuong D Nguyen; John Paul Tutela; Denis Knobel; Oriana Cohen Ba; Stephen M Warren; Pierre B Saadeh |
Publication Detail:
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Type: Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't Date: 2011-05-31 |
Journal Detail:
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Title: Wound repair and regeneration : official publication of the Wound Healing Society [and] the European Tissue Repair Society Volume: 19 ISSN: 1524-475X ISO Abbreviation: Wound Repair Regen Publication Date: 2011 Jul-Aug |
Date Detail:
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Created Date: 2011-07-06 Completed Date: 2011-12-06 Revised Date: 2012-03-02 |
Medline Journal Info:
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Nlm Unique ID: 9310939 Medline TA: Wound Repair Regen Country: United States |
Other Details:
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Languages: eng Pagination: 481-6 Citation Subset: IM |
Copyright Information:
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© 2011 by the Wound Healing Society. |
Affiliation:
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Institute of Reconstructive Plastic Surgery, New York University Langone Medical Center, USA. |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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Animals Diabetes Mellitus / metabolism Disease Models, Animal Fibroblast Growth Factor 2 / genetics, metabolism Gene Silencing* Hypoxia-Inducible Factor 1, alpha Subunit / genetics, metabolism* Mice Neovascularization, Physiologic Procollagen-Proline Dioxygenase / antagonists & inhibitors*, genetics RNA, Messenger / metabolism RNA, Small Interfering* Skin / injuries, metabolism Vascular Endothelial Growth Factor A / genetics, metabolism Wound Healing* |
| Grant Support | |
ID/Acronym/Agency:
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1UL1RR029893-01/RR/NCRR NIH HHS; UL1 RR029893-01/RR/NCRR NIH HHS |
| Chemical | |
Reg. No./Substance:
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0/Hif1a protein, mouse; 0/Hypoxia-Inducible Factor 1, alpha Subunit; 0/RNA, Messenger; 0/RNA, Small Interfering; 0/Vascular Endothelial Growth Factor A; 103107-01-3/Fibroblast Growth Factor 2; EC 1.14.11.2/Egln1 protein, mouse; EC 1.14.11.2/Procollagen-Proline Dioxygenase |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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