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Stromal cell-derived factor-1alpha is cardioprotective after myocardial infarction.

ABSTRACT: 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.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.These findings suggest that SDF-1alpha may serve a tissue-protective and regenerative role for solid organs suffering a hypoxic insult.

SUBMITTER: Saxena A

PROVIDER: S-EPMC2743260 | biostudies-literature | 2008 Apr

REPOSITORIES: biostudies-literature

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Stromal cell-derived factor-1alpha is cardioprotective after myocardial infarction.

Saxena Ankur A Fish Jason E JE White Michael D MD Yu Sangho S Smyth James W P JW Shaw Robin M RM DiMaio J Michael JM Srivastava Deepak D

Circulation 20080421 17

<h4>Background</h4>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.<h4>Methods and res ...[more]

PMID: 18427137

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Project description:After myocardial infarction, there is an inadequate blood supply to the myocardium, and the surrounding borderzone becomes hypocontractile.To develop a clinically translatable therapy, we hypothesized that in a preclinical ovine model of myocardial infarction, the modified endothelial progenitor stem cell chemokine, engineered stromal cell-derived factor 1? analog (ESA), would induce endothelial progenitor stem cell chemotaxis, limit adverse ventricular remodeling, and preserve borderzone contractility.Thirty-six adult male Dorset sheep underwent permanent ligation of the left anterior descending coronary artery, inducing an anteroapical infarction, and were randomized to borderzone injection of saline (n=18) or ESA (n=18). Ventricular function, geometry, and regional strain were assessed using cardiac MRI and pressure-volume catheter transduction. Bone marrow was harvested for in vitro analysis, and myocardial biopsies were taken for mRNA, protein, and immunohistochemical analysis. ESA induced greater chemotaxis of endothelial progenitor stem cells compared with saline (P<0.01) and was equivalent to recombinant stromal cell-derived factor 1? (P=0.27). Analysis of mRNA expression and protein levels in ESA-treated animals revealed reduced matrix metalloproteinase 2 in the borderzone (P<0.05), with elevated levels of tissue inhibitor of matrix metalloproteinase 1 and elastin in the infarct (P<0.05), whereas immunohistochemical analysis of borderzone myocardium showed increased capillary and arteriolar density in the ESA group (P<0.01). Animals in the ESA treatment group also had significant reductions in infarct size (P<0.01), increased maximal principle strain in the borderzone (P<0.01), and a steeper slope of the end-systolic pressure-volume relationship (P=0.01).The novel, biomolecularly designed peptide ESA induces chemotaxis of endothelial progenitor stem cells, stimulates neovasculogenesis, limits infarct expansion, and preserves contractility in an ovine model of myocardial infarction.

Dataset Information

Stromal cell-derived factor-1alpha is cardioprotective after myocardial infarction.

Publications

Stromal cell-derived factor-1alpha is cardioprotective after myocardial infarction.

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