TY - JOUR
T1 - Age-dependent impairment of HIF-1α expression in diabetic mice
T2 - Correction with electroporation-facilitated gene therapy increases wound healing, angiogenesis, and circulating angiogenic cells
AU - Liu, Lixin
AU - Marti, Guy P.
AU - Wei, Xiaofei
AU - Zhang, Xianjie
AU - Zhang, Huafeng
AU - Liu, Ye V.
AU - Nastai, Manuel
AU - Semenza, Gregg L.
AU - Harmon, John W.
PY - 2008/11
Y1 - 2008/11
N2 - Wound healing is impaired in elderly patients with diabetes mellitus. We hypothesized that age-dependent impairment of cutaneous wound healing in db/db diabetic mice: (a) would correlate with reduced expression of the transcription factor hypoxia-inducible factor 1α (HIF-1α) as well as its downstream target genes; and (b) could be overcome by HIF-1α replacement therapy. Wound closure, angiogenesis, and mRNA expression in excisional skin wounds were analyzed and circulating angiogenic cells (CACs) were quantified in db/db mice that were untreated or received electroporation-facilitated HIF-1α gene therapy. HIF-1α mRNA levels in wound tissue were significantly reduced in older (4-6 months) as compared to younger (1.5-2 months) db/db mice. Expression of mRNAs encoding the angiogenic cytokines vascular endothelial growth factor (VEGF), angiopoietin 1 (ANGPT1), ANGPT2, platelet-derived growth factor B (PDGF-B), and placental growth factor (PLGF) was also impaired in wounds of older db/db mice. Intradermal injection of plasmid gWIZ-CA5, which encodes a constitutively active form of HIF-1α, followed by electroporation, induced increased levels of HIF-1α mRNA at the: injection site on day 3 and increased levels of VEGF, PLGF, PDGF-B, and ANGPT2 mRNA on day 7. CACs in peripheral blood increased 10-fold in mice treated with gWIZ-CA5. Wound closure was significantly accelerated in db/db mice treated with gWIZ-CA5 as compared to mice treated with empty vector. Thus, HIF-1α gene therapy corrects the age-dependent impairment of HIF-1α expression, angiogenic cytokine expression, and CACs that contribute to the age-dependent impairment of wound healing in db/db mice.
AB - Wound healing is impaired in elderly patients with diabetes mellitus. We hypothesized that age-dependent impairment of cutaneous wound healing in db/db diabetic mice: (a) would correlate with reduced expression of the transcription factor hypoxia-inducible factor 1α (HIF-1α) as well as its downstream target genes; and (b) could be overcome by HIF-1α replacement therapy. Wound closure, angiogenesis, and mRNA expression in excisional skin wounds were analyzed and circulating angiogenic cells (CACs) were quantified in db/db mice that were untreated or received electroporation-facilitated HIF-1α gene therapy. HIF-1α mRNA levels in wound tissue were significantly reduced in older (4-6 months) as compared to younger (1.5-2 months) db/db mice. Expression of mRNAs encoding the angiogenic cytokines vascular endothelial growth factor (VEGF), angiopoietin 1 (ANGPT1), ANGPT2, platelet-derived growth factor B (PDGF-B), and placental growth factor (PLGF) was also impaired in wounds of older db/db mice. Intradermal injection of plasmid gWIZ-CA5, which encodes a constitutively active form of HIF-1α, followed by electroporation, induced increased levels of HIF-1α mRNA at the: injection site on day 3 and increased levels of VEGF, PLGF, PDGF-B, and ANGPT2 mRNA on day 7. CACs in peripheral blood increased 10-fold in mice treated with gWIZ-CA5. Wound closure was significantly accelerated in db/db mice treated with gWIZ-CA5 as compared to mice treated with empty vector. Thus, HIF-1α gene therapy corrects the age-dependent impairment of HIF-1α expression, angiogenic cytokine expression, and CACs that contribute to the age-dependent impairment of wound healing in db/db mice.
UR - http://www.scopus.com/inward/record.url?scp=51449105857&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=51449105857&partnerID=8YFLogxK
U2 - 10.1002/jcp.21503
DO - 10.1002/jcp.21503
M3 - Article
C2 - 18506785
AN - SCOPUS:51449105857
SN - 0021-9541
VL - 217
SP - 319
EP - 327
JO - Journal of Cellular Physiology
JF - Journal of Cellular Physiology
IS - 2
ER -