Gene therapy with hypoxia-inducible factor 1 alpha in skeletal muscle is cardioprotective in vivo

Aims: Gene therapy of a peripheral organ to protect the heart is clinically attractive. The transcription factor hypoxia-inducible factor 1 alpha (HIF-1 alpha) transactivates cardioprotective genes. We investigated if remote delivery of DNA encoding for HIF-1 alpha is protective against myocardial ischemia-reperfusion injury in vivo. Main methods: DNA encoding for human HIF-1 alpha was delivered to quadriceps muscles of mice. One week later myocardial infarction was induced and four weeks later its size was measured. Echocardiography and in vivo pressure-volume analysis was performed. Coronary vascularization was evaluated through plastic casting. HL-1 cells, transfected with either HIF-1 alpha or HMOX-1 or administered bilirubin or the carbon monoxide (CO) donor CORM-2, were subjected to lipopolysacharide (LPS)-induced cell death to compare the efficacy of treatments. Key findings: After four weeks of reperfusion post infarction, animals pretreated with HIF-1 alpha showed reduced infarct size and left ventricular remodeling (p