Synergy between CD26/DPP-IV Inhibition and G-CSF Improves Cardiac Function after Acute Myocardial Infarction

• Published in: Cell stem cell Vol. 4; no. 4; pp. 313 - 323
• Main Authors: Zaruba, Marc-Michael, Theiss, Hans Diogenes, Vallaster, Markus, Mehl, Ursula, Brunner, Stefan, David, Robert, Fischer, Rebekka, Krieg, Lisa, Hirsch, Eva, Huber, Bruno, Nathan, Petra, Israel, Lars, Imhof, Axel, Herbach, Nadja, Assmann, Gerald, Wanke, Ruediger, Mueller-Hoecker, Josef, Steinbeck, Gerhard, Franz, Wolfgang-Michael
• Format: Journal Article
• Language: English
• Published: Cambridge, MA Elsevier Inc 03.04.2009; Cell Press
• Subjects: Animals; Apoptosis - drug effects; Apoptosis - physiology; Biological and medical sciences; Cardiology. Vascular system; Chemokine CXCL12 - metabolism; Coronary heart disease; Dipeptidyl Peptidase 4 - genetics; Dipeptidyl Peptidase 4 - metabolism; Dipeptidyl-Peptidase IV Inhibitors; Granulocyte Colony-Stimulating Factor - pharmacology; Granulocyte Colony-Stimulating Factor - therapeutic use; Heart; Heart - drug effects; Heart - physiology; Hematopoietic Stem Cell Mobilization; Hematopoietic Stem Cells - drug effects; Hematopoietic Stem Cells - physiology; Kaplan-Meier Estimate; Male; Medical sciences; Mice; Mice, Inbred C57BL; Mice, Knockout; Myocardial Infarction - drug therapy; Myocardial Infarction - enzymology; Myocardial Infarction - physiopathology; Myocarditis. Cardiomyopathies; Neovascularization, Physiologic - drug effects; Neovascularization, Physiologic - physiology; Receptors, CXCR4 - metabolism; STEMCELL; STEMCELL; Heart; Myocardial infarction; Cardiovascular disease; Circulatory system; Inhibition; Coronary heart disease; Myocardial disease
• ISSN: 1934-5909; 1875-9777
• DOI: 10.1016/j.stem.2009.02.013

Ischemic cardiomyopathy is one of the main causes of death, which may be prevented by stem cell-based therapies. SDF-1α is the major chemokine attracting stem cells to the heart. Since SDF-1α is cleaved and inactivated by CD26/dipeptidylpeptidase IV (DPP-IV), we established a therapeutic concept—applicable to ischemic disorders in general—by combining genetic and pharmacologic inhibition of DPP-IV with G-CSF-mediated stem cell mobilization after myocardial infarction in mice. This approach leads to (1) decreased myocardial DPP-IV activity, (2) increased myocardial homing of circulating CXCR-4 + stem cells, (3) reduced cardiac remodeling, and (4) improved heart function and survival. Indeed, CD26 depletion promoted posttranslational stabilization of active SDF-1α in heart lysates and preserved the cardiac SDF-1-CXCR4 homing axis. Therefore, we propose pharmacological DPP-IV inhibition and G-CSF-based stem cell mobilization as a therapeutic concept for future stem cell trials after myocardial infarction.