Gene delivery of the transcription factor hypoxia-inducible factor 1-alpha (HIF-1a) was used to improved cardiac tolerance to induced ischemia in the isolated murine heart.

Equal amounts of plasmid DNA (HIF-1a) were injected into the quadriceps muscle followed by electroporation to enhance DNA-uptake. Control animals were sham-treated with the saline.

Hearts were isolated, Langendorff-perfused and subjected to 40 min` global ischemia and 60 min` reperfusion 1, 4 and 8 weeks after electroporation. An additional series of hearts was examined for vascular responses to phenylephrine and sodium nitropusside. To evaluate possible angiogenesis, fluorescent immunostaining for the endothelial marker CD31 was quantified as 'capillaries' and 'vessels'.

We found an increased local HIF-1a mRNA and nuclear protein expression only in HIF-1a-treated muscles, but not in other organs or shams. Infarct size 1 week after electroporation was 54 ± 13% (mean±SD) in shams, and was reduced to 34 ± 6% in HIF-1a treated animals (p < 0.005). A similar reduction of infarct size was found also 4 and 8 weeks after treatment (p < 0.05). There was an increased coronary flow in the HIF-1a treated animals after 9-10 weeks (p < 0.05), but no difference in contractile and relaxing function. No new capillaries or vessels were formed in the heart at that time point, as opposed to new vessels found in the electroporated and the contralateral skeletal muscle of HIF-1a-treated animals (p < 0.005).

Gene delivery of HIF-1a to skeletal muscles resulted in a local expression of HIF-1a, and reduced myocardial infarct size. Increased coronary flow after gene delivery is not due to a process of angiogenesis.