1. ¹Angiogene Inc., Montreal, QC, Canada
2. ²Division of Cardiology, Duke University Medical Center, Durham, NC

^|[ast]|Employee iof Angiogene Inc.

Abstract

Background: Successful improvement of cardiac function after transplanting skeletal myoblasts into myocardial scar has moved this treatment into clinical trials. A major limitation of this experimental treatment is the death of cells in the hypoxic infarct milieu. Thus, factors which improve angiogenesis and cell survival might increase its efficacy. EPAS1 is a Hypoxia Inducible Factor that regulates genes induced by low oxygen tension, such as the angiogenic factor Vascular Endothelial Growth Factor (VEGF). The hypothesis of this study is that EPAS1 gene transfer will improve the angiogenic potential of myoblasts in myocardial scar and thus the efficacy of the treatment. Methods: Human skeletal myoblasts were transduced with an adenovirus expressing EPAS1 and VEGF was measured by ELISA. Microarrays were used to document the profile of gene induction. Myoblasts and EPAS1 modified myoblasts were implanted into incryoinjured left ventricle of immunodeficient mice (N=8 per group). Cardiac function was assessed at day 0 and 28 by magnetic resonance imaging. Fluorescent lectin was infused in the circulation prior to sacrifice and vessels in scar were evaluated by histology. Results: There was a 20-fold VEGF induction upon EPAS1 gene transfer. Other angiogenic genes (PlGF, IL-8, and LIF) and cardioprotective genes (LIF-R, cardiotrophin 1 and adrenomedullin) were also induced by EPAS1. Vessel density and cardiac function improvement were superior in the EPAS1 modified myoblasts group. Conclusions: EPAS1 gene transfer increases the expression of angiogenic and cardioprotective genes and enhances the functional impact of myoblasts in scar, presumably by promoting angiogenesis and cell survival (See Figure 1).