L9	A possible role for hypoxia-inducible factor 1α in protection against reperfusion injury.
G.Valen
University of Oslo, Institute of Basic Meical Science, Department of Physiology, Oslo, NO.

Hypoxia-inducible factor 1 alpha (HIF-1α) is the most important transcription factor for the regulation of oxygen homeostasis. It is activated induced by hypoxia in all nucleated cells, and regulates some 30 genes involved in increasing oxygen delivery to tissue by angiogenesis, regulation of vascular tone, oxygen transport, supply, and uptake, glycolysis, and cell survival. HIF-1α is activated by hypoxic preconditioning, and may contribute to increased cell survival in this context through increase of heme oxygenase-1. However, HIF-1α is not activated by classic ischemic preconditioning of human hearts, in contrast to the transcription factor nuclear factor kappa B. We investigated if gene delivery of HIF-1α could improve reperfusion injury. Naked DNA was injected into murine quadriceps muscle, followed by electroporation to enhance uptake of DNA. This resulted in a local, lasting expression of HIF-1α in the skeletal muscle as evaluated by immunoblot and real time PCR, with no expression of the delivered plasmid in any other organ. Hearts were isolated, Langendorff-perfused and subjected to global ischemia and reperfusion, 1, 4 and 8 weeks after electroporation. Hearts of mice pretreated with DNA for HIF-1α had smaller infarcts than sham treated animals. Hearts of HIF-1α treated mice had new vessel formation, evident as an increased amount of CD31 positive cells. We are currently evaluating if also other organs have new vessel formation. Possibly a more cardiospecific delivery of HIF-1α would optimize the therapeutic potential of this factor.

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