1. ¹Department of Pediatrics, College of Medicine and All Children's Hospital Research Institute, University of South Florida, St Petersburg, FL, USA
2. ²Anaspec, Inc., San Jose, CA, USA
3. ³Division of Nephrology, University of Alabama at Birmingham, Birmingham, AL, USA
4. ⁴Department of Physiology, University of Florida, Gainesville, FL, USA

Correspondence: Dr MI Phillips, Department of Pediatrics, College of Medicine and All Children's Hospital Research Institute, University of South Florida, 140 7th Ave S, CRI 2005, St Petersburg, FL 33701, USA

⁵These authors contributed equally to this work

Received 9 September 2004; Accepted 17 January 2005; Published online 31 March 2005.

Abstract

Hypoxia represents an endogenous pathophysiological signal underlying cell growth, adaptation and death in a variety of diseases, including ischemic heart diseases, stroke and solid tumors. A vigilant vector system depends on a gene switch which can sense the hypoxia signal occurring in ischemic events and turn on/off protective gene expressions when necessary. This system uses the oxygen-dependent degradation domain derived from hypoxia-inducible factor 1 as the hypoxia sensor and a double-vector system as signal amplifier. For treating ischemic heart diseases, a cardiac-specific MLC-2v promoter is used to deliver transgenes specifically to the heart. When tested in cardiomyocyte cultures, it produced a rapid and robust gene induction upon exposure to low oxygen. In a mouse model for myocardial infarction, the vigilant vectors turned on therapeutic genes such as heme oxygenase-1 in response to ischemia, significantly reduced apoptosis in the infarct area and improved cardiac functions. The hypoxia-regulated gene transfer afforded by the vigilant vectors may provide a powerful tool for delivering therapeutic proteins specifically to ischemic tissues with optimal physiological control.