Abstract
Hematopoietic progenitor CD133(+)/c-kit(+) cells have been shown to be involved in myocardial healing following myocardial infarction (MI). Previously we demonstrated that angiopoietin-1(Ang-1) is beneficial in the repair of diabetic infarcted hearts. We now investigate whether Ang-1 affects CD133(+)/c-kit(+) cell recruitment to the infarcted myocardium thereby mediating cardiac repair in type II (db/db) diabetic mice. db/db mice were administered either adenovirus Ang-1 (Ad-Ang-1) or Ad-β-gal systemically immediately after ligation of the left anterior descending coronary artery (LAD). Overexpression of Ang-1 resulted in a significant increase in CXCR-4/SDF-1α expression and promoted CD133(+)/c-kit(+), CD133(+)/CXCR-4(+) and CD133(+)/SDF-1α(+) cell recruitment into ischemic hearts. Overexpression of Ang-1 led to significant increases in number of CD31(+) and smooth muscle-like cells and VEGF expression in bone marrow (BM). This was accompanied by significant decreases in cardiac apoptosis and fibrosis and an increase in myocardial capillary density. Ang-1 also upregulated Jagged-1, Notch3 and apelin expression followed by increases in arteriole formation in the infarcted myocardium. Furthermore, overexpression of Ang-1 resulted in a significant improvement of cardiac functional recovery after 14 days of ischemia. Our data strongly suggest that Ang-1 attenuates cardiac apoptosis and promotes cardiac repair by a mechanism involving in promoting CD133(+)/c-kit(+) cells and angiogenesis in diabetic db/db mouse infarcted hearts.
Publication types
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Research Support, N.I.H., Extramural
MeSH terms
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AC133 Antigen
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Actins / metabolism
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Adipokines
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Angiopoietin-1 / metabolism*
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Animals
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Antigens, CD / metabolism*
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Apelin
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Apoptosis*
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Bone Marrow / metabolism
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Bone Marrow / pathology
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Calcium-Binding Proteins / metabolism
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Capillaries / metabolism
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Capillaries / pathology
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Capillaries / physiopathology
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Cardiomegaly / complications
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Cardiomegaly / metabolism
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Cardiomegaly / pathology
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Cardiomegaly / physiopathology
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Cell Movement
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Chemokine CXCL12 / metabolism
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Diabetes Mellitus, Type 2 / complications
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Diabetes Mellitus, Type 2 / metabolism
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Diabetes Mellitus, Type 2 / pathology
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Diabetes Mellitus, Type 2 / physiopathology
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Endomyocardial Fibrosis / complications
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Endomyocardial Fibrosis / metabolism
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Endomyocardial Fibrosis / pathology
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Endomyocardial Fibrosis / physiopathology
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Glycoproteins / metabolism*
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Heart Function Tests
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Hematopoietic Stem Cells / cytology
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Intercellular Signaling Peptides and Proteins / metabolism
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Jagged-1 Protein
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Membrane Proteins / metabolism
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Mice
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Myocardial Infarction / complications
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Myocardial Infarction / metabolism
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Myocardial Infarction / pathology*
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Myocardial Infarction / physiopathology
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Myocardium / metabolism*
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Myocardium / pathology*
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Peptides / metabolism*
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Platelet Endothelial Cell Adhesion Molecule-1 / metabolism
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Proto-Oncogene Proteins c-kit / metabolism*
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Receptor, Notch3
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Receptors, CXCR4 / metabolism
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Receptors, Notch / metabolism
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Serrate-Jagged Proteins
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Signal Transduction
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Up-Regulation
Substances
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AC133 Antigen
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Actins
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Adipokines
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Angiopoietin-1
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Antigens, CD
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Apelin
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Apln protein, mouse
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Calcium-Binding Proteins
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Chemokine CXCL12
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Glycoproteins
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Intercellular Signaling Peptides and Proteins
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Jag1 protein, mouse
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Jagged-1 Protein
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Membrane Proteins
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Notch3 protein, mouse
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Peptides
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Platelet Endothelial Cell Adhesion Molecule-1
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Prom1 protein, mouse
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Receptor, Notch3
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Receptors, CXCR4
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Receptors, Notch
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Serrate-Jagged Proteins
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alpha-smooth muscle actin, mouse
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Proto-Oncogene Proteins c-kit