HIF-regulated HO-1 gene transfer improves the post-ischemic limb recovery and diminishes TLR-triggered immune responses - Effects modified by concomitant VEGF overexpression

The concept of hypoxia-regulated gene therapy. Under conditions of decreased oxygen supply (for e.g. hindlimb ischemia) HIF-1α is stabilized and enters the nucleus where it binds the HIF-1β subunit. This heterodimer activates the HRE sequence within the promoter region located upstream of HO-1 and VEGF coding sequence and leads to upregulation of both transgene products and the therapeutic effects. HIF-1α - hypoxia inducible factor-1α; HRE - hypoxia response element; minCMV - minimal cytomegalovirus; HO-1 - heme oxygenase-1; VEGF - vascular endothelial growth factor; IRES - internal ribosome entry site; TLR - toll-like receptor.208