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


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.


RESULTS
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).


CONCLUSIONS
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.
Dept. of Physiology, Institute of Basic Medical Sciences, University of Oslo, Oslo, Norway.
Gabor
G
Czibik
Jørgen
J
Gravning
Vladimir
V
Martinov
Bushra
B
Ishaq
Eirunn
E
Knudsen
Håvard
H
Attramadal
Guro
G
Valen
D000199:Actins / Q000378:metabolism; D000818:Animals; D001663:Bilirubin / Q000097:blood; D001835:Body Weight; D018929:Cell Culture Techniques; D002470:Cell Survival / Q000187:drug effects / Q000235:genetics; D003331:Coronary Vessels / Q000000981:diagnostic imaging; D004247:DNA / Q000008:administration & dosage / Q000235:genetics; D004195:Disease Models, Animal; D004452:Echocardiography; D005434:Flow Cytometry; D015316:Genetic Therapy / Q000379:methods*; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics*; D008070:Lipopolysaccharides / Q000494:pharmacology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018482:Muscle, Skeletal / Q000378:metabolism*; D009203:Myocardial Infarction / Q000000981:diagnostic imaging / Q000235:genetics / Q000628:therapy*; D032383:Myocytes, Cardiac / Q000166:cytology / Q000187:drug effects; D018919:Neovascularization, Physiologic / Q000235:genetics; D009929:Organ Size; D020133:Reverse Transcriptase Polymerase Chain Reaction; D016019:Survival Analysis; D014162:Transfection; D020257:Ventricular Remodeling / Q000235:genetics / Q000502:physiology
D000199:Actins; C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D008070:Lipopolysaccharides; D004247:DNA; D001663:Bilirubin