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

Life Sci. 2011 Mar 14;88(11-12):543-50. doi: 10.1016/j.lfs.2011.01.006. Epub 2011 Jan 14.


Aims: 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.

Main methods: 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.

Key findings: 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).

Significance: 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Actins / metabolism
  • Animals
  • Bilirubin / blood
  • Body Weight
  • Cell Culture Techniques
  • Cell Survival / drug effects
  • Cell Survival / genetics
  • Coronary Vessels / diagnostic imaging
  • DNA / administration & dosage
  • DNA / genetics
  • Disease Models, Animal
  • Echocardiography
  • Flow Cytometry
  • Genetic Therapy / methods*
  • Hypoxia-Inducible Factor 1, alpha Subunit / genetics*
  • Lipopolysaccharides / pharmacology
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Muscle, Skeletal / metabolism*
  • Myocardial Infarction / diagnostic imaging
  • Myocardial Infarction / genetics
  • Myocardial Infarction / therapy*
  • Myocytes, Cardiac / cytology
  • Myocytes, Cardiac / drug effects
  • Neovascularization, Physiologic / genetics
  • Organ Size
  • Reverse Transcriptase Polymerase Chain Reaction
  • Survival Analysis
  • Transfection
  • Ventricular Remodeling / genetics
  • Ventricular Remodeling / physiology


  • Actins
  • HIF1A protein, human
  • Hypoxia-Inducible Factor 1, alpha Subunit
  • Lipopolysaccharides
  • DNA
  • Bilirubin