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<0.05, respectively). Fractional shortening was preserved in mice pretreated with HIF-1 alpha (p<0.05). Invasive hemodynamic parameters indicated preserved left ventricular function after HIF-1 alpha (p<0.05), which also induced coronary vascularization (p<0.05). HIF-1 alpha downstream target heme oxygenase 1 (HMOX-1) was upregulated in skeletal muscle, while serum bilirubin was increased. Transfection of HL-1 cells with HIF-1 alpha or HMOX-1 and administration of bilirubin or CORM-2 comparably salvaged cells from lipopolysacharide (LPS)-induced cell death (all p<0.05). Significance: HIF-1 alpha gene delivery to skeletal muscle preceding myocardial ischemia reduced infarct size and postischemic remodeling accompanied by an improved cardiac function and vascularization. Similar to HIF-1 alpha, HMOX-1, bilirubin and CO were protective against LPS-induced injury. This observation may have clinical potential. (C) 2011 Elsevier Inc. All rights reserved.