A hypoxia-inducible vigilant vector system for activating therapeutic genes in ischemia

Academic Article

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 1α 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. © 2005 Nature Publishing Group. All rights reserved.
  • Digital Object Identifier (doi)

    Author List

  • Tang YL; Tang Y; Zhang YC; Agarwal A; Kasahara H; Qian K; Shen L; Phillips MI
  • Start Page

  • 1163
  • End Page

  • 1170
  • Volume

  • 12
  • Issue

  • 15