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Gene therapy of endothelial nitric oxide synthase and manganese superoxide dismutase restores delayed wound healing in type 1 diabetic mice.
- Source :
-
Circulation [Circulation] 2004 Oct 19; Vol. 110 (16), pp. 2484-93. Date of Electronic Publication: 2004 Jul 19. - Publication Year :
- 2004
-
Abstract
- Background: Nitric oxide (NO) deficiency contributes to diabetic wound healing impairment. The present study tested the hypothesis that increased cutaneous superoxide (O2-) levels in type 1 diabetic mice cause NO deficiency and delayed wound healing.<br />Methods and Results: Wound healing was markedly delayed in streptozotocin-induced type 1 diabetic mice compared with the normal controls. There were significantly reduced levels of endothelial NO synthase (eNOS) protein and constitutive NOS activity in diabetic wounds, whereas O2- levels were markedly increased. A single regimen of cutaneous gene therapy of eNOS or manganese superoxide dismutase (MnSOD) restored such healing delay, with a concomitant suppression of wound O2- levels and augmentation of both eNOS protein and constitutive NOS activity. Gene therapy of MnSOD also increased cutaneous MnSOD activity. Cutaneous O2- levels were also increased in Ins2(Akita) diabetic mice. In vitro glucose treatment of cutaneous tissues from normal mice for 24 hours increased O2- levels in a concentration-dependent manner. The enhanced cutaneous O2- levels induced by high glucose in both normal and diabetic mice were abolished by the NADPH oxidase inhibitor apocynin and the protein kinase C inhibitor chelerythrine. Furthermore, ex vivo gene transfer of dominant-negative HA-tagged N17Rac1, which inhibits NADPH oxidase subunit Rac1, significantly inhibited cutaneous O2- formation induced by high glucose in both normal and Ins2(Akita) diabetic mice.<br />Conclusions: These results indicate that hyperglycemia augments cutaneous O2- levels, at least in part, via NADPH oxidase and protein kinase C pathways, resulting in impaired wound healing in type 1 diabetic mice. Gene therapy strategies aimed at restoring cutaneous NO bioavailability may provide an effective means to ameliorate delayed diabetic wound healing.
- Subjects :
- Acetophenones pharmacology
Adenoviridae genetics
Alkaloids
Animals
Benzophenanthridines
Biological Availability
Diabetes Mellitus, Experimental complications
Diabetes Mellitus, Experimental physiopathology
Enzyme Induction
Glucose pharmacology
Male
Mice
Mice, Inbred C57BL
NADPH Oxidases antagonists & inhibitors
Nitric Oxide deficiency
Nitric Oxide Synthase biosynthesis
Nitric Oxide Synthase genetics
Nitric Oxide Synthase Type II
Nitric Oxide Synthase Type III
Nitrites analysis
Oxidative Stress
Phenanthridines pharmacology
Protein Kinase C antagonists & inhibitors
Recombinant Fusion Proteins physiology
Signal Transduction
Skin chemistry
Skin injuries
Superoxide Dismutase genetics
Superoxides metabolism
rac1 GTP-Binding Protein antagonists & inhibitors
rac1 GTP-Binding Protein physiology
Diabetes Mellitus, Experimental therapy
Genetic Therapy
Genetic Vectors therapeutic use
NADPH Oxidases physiology
Nitric Oxide physiology
Nitric Oxide Synthase physiology
Protein Kinase C physiology
Superoxide Dismutase physiology
Wound Healing physiology
Subjects
Details
- Language :
- English
- ISSN :
- 1524-4539
- Volume :
- 110
- Issue :
- 16
- Database :
- MEDLINE
- Journal :
- Circulation
- Publication Type :
- Academic Journal
- Accession number :
- 15262829
- Full Text :
- https://doi.org/10.1161/01.CIR.0000137969.87365.05