The study describes the development of a vigilant vector for protection against myocardial ischemia. The concept is a vector that can be systemically injected that waits in the heart for an ischemic attack. The vector then switches on cardioprotective genes specifically in the heart to save the cells from apoptosis and maintain cardiac performance. Using the adenoassociated virus (AAV), we have developed a double vector system (a sensor and an effector vector), that has a gene switch responsive to hypoxia, and a myosin light chain 2 ventricular (MLC-2v) promoter so that expression only occurs in the heart. The gene switch causes expression of therapeutic genes, such as heme oxygenase 1 (HO-1) and super oxide dismutase (SOD), to provide cardioprotective effects. The sensor AAV contains an oxygen-dependent domain (ODD) of hypoxia-inducible factor-1 (HIF-1α). The vector is switched on by low oxygen (<1%) and switched off by normoxia. To amplify the cardioprotective effect, an amplification system is added to the gene switch. This system consists of the yeast gene, GAL4, together with the NFκβ protein P65. The MLC-2v promoter drives the expression of a fusion protein of GAL4/p65 exponentially with low oxygen. This fusion protein binds to the effector component of the amplification system in a second AAV or plasmid. The effector AAV has a GAL4 upstream sequence-binding site. Binding to this site by the fusion protein causes the expression of cardioprotective genes at a rate that increases exponentially as oxygen levels are reduced. This has been successfully tested in vitro in myocardial cells, including both embryonic prenatal and adult rat cardiomyocytes; and in vivo in mouse myocardial ischemic hearts.