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Prophylactic gene therapy with human tissue kallikrein ameliorates limb ischemia recovery in type 1 diabetic mice.
- Source :
-
Diabetes [Diabetes] 2004 Apr; Vol. 53 (4), pp. 1096-103. - Publication Year :
- 2004
-
Abstract
- Diabetes macro- and microvascular disease causes tissue hypoperfusion. This deficit, together with a failure to mount an adequate angiogenic response, might explain why vascular occlusion evolves more severely among diabetic patients. The present study investigated whether prophylactic gene therapy with human tissue kallikrein (hTK) may protect diabetic limbs from the consequences of supervening ischemia. Vehicle (saline) or an adenovirus carrying the gene for either hTK (Ad.hTK) or luciferase (Ad.Luc) was injected into left adductor muscles of streptozotocin-induced type 1 diabetic mice 2 weeks before operative occlusion of the ipsilateral femoral artery. Saline-injected nondiabetic mice served as controls. Hindlimb blood flow recovery was analyzed sequentially over the 2 weeks after ischemia induction. At necroscopy, microvessel density and endothelial cell proliferation and apoptosis were quantified in skeletal muscles. We found that limb perfusion recovery of saline-injected type 1 diabetic mice is delayed because of insufficient reparative neovascularization and excessive activation of endothelial cell apoptosis. By contrast, prophylactic Ad.hTK renewed the ability to mount an appropriate neovascularization response to ischemia, suppressed apoptosis, and upregulated endothelial nitric oxide synthase expression. Ultimately, correction of diabetic endotheliopathy by Ad.hTK allowed proper perfusion recovery as seen in nondiabetic mice. These discoveries disclose new therapeutic options for the treatment of diabetic complications.
- Subjects :
- Animals
Arterioles drug effects
Arterioles growth & development
Diabetes Mellitus, Experimental therapy
Extremities blood supply
Humans
Ischemia etiology
Ischemia therapy
Luciferases genetics
Male
Mice
Nitric Oxide Synthase genetics
Nitric Oxide Synthase Type II
Nitric Oxide Synthase Type III
Reference Values
Time Factors
Diabetes Mellitus, Type 1 therapy
Diabetic Angiopathies therapy
Genetic Therapy methods
Tissue Kallikreins genetics
Subjects
Details
- Language :
- English
- ISSN :
- 0012-1797
- Volume :
- 53
- Issue :
- 4
- Database :
- MEDLINE
- Journal :
- Diabetes
- Publication Type :
- Academic Journal
- Accession number :
- 15047627
- Full Text :
- https://doi.org/10.2337/diabetes.53.4.1096