Age-dependent impairment of HIF-1α expression in diabetic mice:: Correction with electroporation-facilitated gene therapy increases wound healing, angiogenesis, and circulating angiogenic cells

被引:139
作者
Liu, Lixin [1 ]
Marti, Guy P. [1 ]
Wei, Xiaofei [2 ,3 ,4 ,5 ,6 ,7 ]
Zhang, Xianjie [1 ]
Zhang, Huafeng [2 ,3 ,4 ,5 ,6 ,7 ]
Liu, Ye V. [2 ,3 ,4 ,5 ,6 ,7 ]
Nastai, Manuel [1 ]
Semenza, Gregg L. [2 ,3 ,4 ,5 ,6 ,7 ]
Harmon, John W. [1 ]
机构
[1] Johns Hopkins Univ, Sch Med, Sect Surg Sci, Baltimore, MD USA
[2] Johns Hopkins Univ, Sch Med, Inst Cell Engn, Vasc Program, Baltimore, MD USA
[3] Johns Hopkins Univ, Sch Med, Dept Pediat, Baltimore, MD 21205 USA
[4] Johns Hopkins Univ, Sch Med, Dept Med, Baltimore, MD 21205 USA
[5] Johns Hopkins Univ, Sch Med, Dept Oncol, Baltimore, MD 21205 USA
[6] Johns Hopkins Univ, Sch Med, Dept Radiat Oncol, Baltimore, MD USA
[7] Johns Hopkins Univ, Sch Med, McKusick Nathans Inst Genet Med, Baltimore, MD USA
关键词
D O I
10.1002/jcp.21503
中图分类号
Q2 [细胞生物学];
学科分类号
071009 ; 090102 ;
摘要
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 1 alpha (HIF-1 alpha) as well as its downstream target genes; and (b) could be overcome by HIF-1 alpha 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-1 alpha gene therapy. HIF-1 alpha 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-1 alpha, followed by electroporation, induced increased levels of HIF-1 alpha 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 created with empty vector. Thus, HIF-1 alpha gene therapy corrects the age-dependent impairment of HIF-1 alpha expression, angiogenic cytokine expression, and CACs that contribute to the age-dependent impairment of wound healing in db/db mice.
引用
收藏
页码:319 / 327
页数:9
相关论文
共 49 条
[11]   Animal models for wound repair [J].
Davidson, JM .
ARCHIVES OF DERMATOLOGICAL RESEARCH, 1998, 290 (Suppl 1) :S1-S11
[12]  
Elson DA, 2000, CANCER RES, V60, P6189
[13]   Number and function of endothelial progenitor cells as a marker of severity for diabetic vasculopathy [J].
Fadini, Gian Paolo ;
Sartore, Saverio ;
Albiero, Mattia ;
Baesso, Ilenia ;
Murphy, Ellen ;
Menegolo, Mirko ;
Grego, Franco ;
de Kreutzenberg, Saula Vigili ;
Tiengo, Antonio ;
Agostini, Carlo ;
Avogaro, Angelo .
ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY, 2006, 26 (09) :2140-2146
[14]   Circulating endothelial progenitor cells are reduced in peripheral vascular complications of type 2 diabetes mellitus [J].
Fadini, GP ;
Miorin, M ;
Facco, M ;
Bonamico, S ;
Baesso, I ;
Grego, F ;
Menegolo, M ;
de Kreutzenberg, SV ;
Tiengo, A ;
Agostini, C ;
Avogaro, A .
JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY, 2005, 45 (09) :1449-1457
[15]   Wound healing enhancement: Electroporation to address a classic problem of military medicine [J].
Ferguson, M ;
Byrnes, C ;
Sun, L ;
Marti, G ;
Bonde, P ;
Duncan, M ;
Harmon, JW .
WORLD JOURNAL OF SURGERY, 2005, 29 (Suppl 1) :S55-S59
[16]  
Forsythe JA, 1996, MOL CELL BIOL, V16, P4604
[17]   REGULATION OF VASCULAR ENDOTHELIAL GROWTH-FACTOR EXPRESSION IN CULTURED KERATINOCYTES - IMPLICATIONS FOR NORMAL AND IMPAIRED WOUND-HEALING [J].
FRANK, S ;
HUBNER, G ;
BREIER, G ;
LONGAKER, MT ;
GREENHALGH, DG ;
WERNER, S .
JOURNAL OF BIOLOGICAL CHEMISTRY, 1995, 270 (21) :12607-12613
[18]   Insulin-like growth factor 1 induces hypoxia-inducible factor 1-mediated vascular endothelial growth factor expression, which is dependent on MAP kinase and phosphatidylinositol 3-kinase signaling in colon cancer cells [J].
Fukuda, R ;
Hirota, K ;
Fan, F ;
Do Jung, Y ;
Ellis, LM ;
Semenza, GL .
JOURNAL OF BIOLOGICAL CHEMISTRY, 2002, 277 (41) :38205-38211
[19]  
Fukuda R, 2003, CANCER RES, V63, P2330
[20]   Aging and wound healing [J].
Gosain, A ;
Luisa, MD ;
DiPietro, A .
WORLD JOURNAL OF SURGERY, 2004, 28 (03) :321-326