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Prophylactic gene therapy with human tissue kallikrein ameliorates limb ischemia recovery in type 1 diabetic mice

Emanueli, Costanza and Graiani, Gallia and Salis, Maria Bonaria and Gadau, Sergio Domenico and Desortes, Elisa and Madeddu, Paolo Roberto (2004) Prophylactic gene therapy with human tissue kallikrein ameliorates limb ischemia recovery in type 1 diabetic mice. Diabetes, Vol. 53 (4), p. 1096-1103. Article.

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DOI: 10.2337/diabetes.53.4.1096

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.

Item Type:Article
ID Code:7750
Status:Published
Refereed:Yes
Uncontrolled Keywords:Prophylactic gene therapy, human tissue kallikrein (hTK), diabetes
Subjects:Area 07 - Scienze agrarie e veterinarie > VET/01 Anatomia degli animali domestici
Divisions:002 Altri enti e centri di ricerca del Nord Sardegna > Porto Conte Ricerche, Alghero
001 Università di Sassari > 01 Dipartimenti > Biologia animale
002 Altri enti e centri di ricerca del Nord Sardegna > Istituto nazionale biostrutture e biosistemi, Unità di ricerca, Sassari
Publisher:American Diabetes Association
Deposited On:06 Jul 2012 10:02

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