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

• Published in: Life sciences (1973) 2011-03, Vol.88 (11), p.543-550
• Main Authors: Czibik, Gabor, Gravning, Jørgen, Martinov, Vladimir, Ishaq, Bushra, Knudsen, Eirunn, Attramadal, Håvard, Valen, Guro
• Format: Article
• Language: English
• Subjects: Actins - metabolism; Angiogenesis; Animals; Bilirubin; Bilirubin - blood; blood serum; Body Weight; Carbon monoxide; Cardiac muscle; cardiac output; Cardioprotection; Cell Culture Techniques; Cell death; Cell Survival - drug effects; Cell Survival - genetics; Coronary Vessels - diagnostic imaging; Disease Models, Animal; DNA; DNA - administration & dosage; DNA - genetics; Echocardiography; Flow Cytometry; Gene therapy; genes; Genetic Therapy - methods; Heart; heme oxygenase (biliverdin-producing); Heme oxygenase (decyclizing); Hemodynamics; HIF-1α; HMOX-1; humans; Hypoxia-inducible factor 1; Hypoxia-inducible factor 1 alpha; Hypoxia-Inducible Factor 1, alpha Subunit - genetics; infarction; Injuries; Lipopolysaccharides - pharmacology; Male; Mice; Mice, Inbred C57BL; Muscle, Skeletal - metabolism; muscles; myocardial infarction; Myocardial Infarction - diagnostic imaging; Myocardial Infarction - genetics; Myocardial Infarction - therapy; Myocytes, Cardiac - cytology; Myocytes, Cardiac - drug effects; Neovascularization, Physiologic - genetics; Organ Size; quadriceps muscle; Reperfusion; Reverse Transcriptase Polymerase Chain Reaction; Skeletal muscle; Survival Analysis; Transcription factors; Transfection; vascularization; Ventricle; Ventricular Remodeling - genetics; Ventricular Remodeling - physiology
• ISSN: 0024-3205; 1879-0631
• DOI: 10.1016/j.lfs.2011.01.006

Gene therapy of a peripheral organ to protect the heart is clinically attractive. The transcription factor hypoxia-inducible factor 1 alpha (HIF-1α) transactivates cardioprotective genes. We investigated if remote delivery of DNA encoding for HIF-1α is protective against myocardial ischemia–reperfusion injury in vivo. DNA encoding for human HIF-1α 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-1α 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. After four weeks of reperfusion post infarction, animals pretreated with HIF-1α showed reduced infarct size and left ventricular remodeling (p < 0.05, respectively). Fractional shortening was preserved in mice pretreated with HIF-1α (p < 0.05). Invasive hemodynamic parameters indicated preserved left ventricular function after HIF-1α (p < 0.05), which also induced coronary vascularization (p < 0.05). HIF-1α downstream target heme oxygenase 1 (HMOX-1) was upregulated in skeletal muscle, while serum bilirubin was increased. Transfection of HL-1 cells with HIF-1α or HMOX-1 and administration of bilirubin or CORM-2 comparably salvaged cells from lipopolysacharide (LPS)-induced cell death (all p < 0.05). HIF-1α 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-1α, HMOX-1, bilirubin and CO were protective against LPS-induced injury. This observation may have clinical potential.