Oxygen dependent degradation domain mediated hypoxia specific VEGF gene therapy for ischemic heart disease

Abstract

Gene therapy with VEGF is a promising strategy for the treatment of cardiovascular diseases. Howeve,r uncontrolled expression of exogenous vEGF could cause adverse effects on normal tissues. Therefore, the controllable gene expression systems are required for safe and successful gene therpay. In this study, hypxoia-inducible luciferase expression vector with the oxygen dependent degradation (ODD) domain and the erythropoietin (Epo) enhancer, pEpo-Sv-Luc-ODD, was constructed. The ODD domain was used for post-translational induction of VEGF expression under hxpoxia. pEpo-SV-Luc-ODD increased gene expression in HEK 293 cells under hypoxia. The hypxoia-inducible VEGF expression vector, pEpo-SV-VEGF-ODD, was constructed and injected into rat ischemic myocardium. Five days after gene transfer, highest VEGF expression was obtained in the pEpo-SV-VEGF-ODD group. Masson`s trichrome staining and alpha-smooth msucle actin staining showed significantly less fibrotic areas in the pEpo-SV-VEGF-ODD group. In addition, apoptoti ccells of cardiomyocytes was reduced in the pEpo-SV-VEGF-ODD group. There results demonstrate in vivo efficacy of an ODD mediated hypoxia-inducible system in ischemic myocardium.