BACKGROUND: Heart disease is a leading cause of mortality throughout the world. Tissue damage from vascular occlusive events results in the replacement of contractile myocardium by nonfunctional scar tissue. The potential of new technologies to regenerate damaged myocardium is significant, although cell-based therapies must overcome several technical barriers. One possible cell-independent alternative is the direct administration of small proteins to damaged myocardium. METHODS AND RESULTS: Here we show that the secreted signaling protein stromal cell-derived factor-1alpha (SDF-1alpha), which activates the cell-survival factor protein kinase B (PKB/Akt) via the G protein-coupled receptor CXCR4, protected tissue after an acute ischemic event in mice and activated Akt within endothelial cells and myocytes of the heart. Significantly better cardiac function than in control mice was evident as early as 24 hours after infarction as well as at 3, 14, and 28 days after infarction. Prolonged survival of hypoxic myocardium was followed by an increase in levels of vascular endothelial growth factor protein and neoangiogenesis. Consistent with improved cardiac function, mice exposed to SDF-1alpha demonstrated significantly decreased scar formation than control mice. CONCLUSIONS: These findings suggest that SDF-1alpha may serve a tissue-protective and regenerative role for solid organs suffering a hypoxic insult.
BACKGROUND:Heart disease is a leading cause of mortality throughout the world. Tissue damage from vascular occlusive events results in the replacement of contractile myocardium by nonfunctional scar tissue. The potential of new technologies to regenerate damaged myocardium is significant, although cell-based therapies must overcome several technical barriers. One possible cell-independent alternative is the direct administration of small proteins to damaged myocardium. METHODS AND RESULTS: Here we show that the secreted signaling protein stromal cell-derived factor-1alpha (SDF-1alpha), which activates the cell-survival factor protein kinase B (PKB/Akt) via the G protein-coupled receptor CXCR4, protected tissue after an acute ischemic event in mice and activated Akt within endothelial cells and myocytes of the heart. Significantly better cardiac function than in control mice was evident as early as 24 hours after infarction as well as at 3, 14, and 28 days after infarction. Prolonged survival of hypoxic myocardium was followed by an increase in levels of vascular endothelial growth factor protein and neoangiogenesis. Consistent with improved cardiac function, mice exposed to SDF-1alpha demonstrated significantly decreased scar formation than control mice. CONCLUSIONS: These findings suggest that SDF-1alpha may serve a tissue-protective and regenerative role for solid organs suffering a hypoxic insult.
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