title: Early upregulation of myocardial CXCR4 expression is critical for dimethyloxalylglycine-induced cardiac improvement in acute myocardial infarction.
abstract: The stromal cell-derived factor-1 (SDF-1):CXCR4 is important in myocardial repair. In this study we tested the hypothesis that early upregulation of cardiomyocyte CXCR4 (CM-CXCR4) at a time of high myocardial SDF-1 expression could be a strategy to engage the SDF-1:CXCR4 axis and improve cardiac repair. The effects of the hypoxia inducible factor (HIF) hydroxylase inhibitor dimethyloxalylglycine (DMOG) on CXCR4 expression was tested on H9c2 cells. In mice a myocardial infarction (MI) was produced in CM-CXCR4 null and wild-type controls. Mice were randomized to receive injection of DMOG (DMOG group) or saline (Saline group) into the border zone after MI. Protein and mRNA expression of CM-CXCR4 were quantified. Echocardiography was used to assess cardiac function. During hypoxia, DMOG treatment increased CXCR4 expression of H9c2 cells by 29 and 42% at 15 and 24 h, respectively. In vivo DMOG treatment increased CM-CXCR4 expression at 15 h post-MI in control mice but not in CM-CXCR4 null mice. DMOG resulted in increased ejection fraction in control mice but not in CM-CXCR4 null mice 21 days after MI. Consistent with greater cardiomyocyte survival with DMOG treatment, we observed a significant increase in cardiac myosin-positive area within the infarct zone after DMOG treatment in control mice, but no increase in CM-CXCR4 null mice. Inhibition of cardiomyocyte death in MI through the stabilization of HIF-1α requires downstream CM-CXCR4 expression. These data suggest that engagement of the SDF-1:CXCR4 axis through the early upregulation of CM-CXCR4 is a strategy for improving cardiac repair after MI.
authors.affiliation: Department of Integrative Medical Sciences, Northeast Ohio Medical University, Rootstown, and.
authors.forename: Mari
authors.initials: M
authors.lastname: Mayorga
authors.affiliation: Department of Integrative Medical Sciences, Northeast Ohio Medical University, Rootstown, and.
authors.forename: Matthew
authors.initials: M
authors.lastname: Kiedrowski
authors.affiliation: Department of Integrative Medical Sciences, Northeast Ohio Medical University, Rootstown, and.
authors.forename: Patricia
authors.initials: P
authors.lastname: Shamhart
authors.affiliation: Department of Integrative Medical Sciences, Northeast Ohio Medical University, Rootstown, and.
authors.forename: Farhad
authors.initials: F
authors.lastname: Forudi
authors.affiliation: Department of Integrative Medical Sciences, Northeast Ohio Medical University, Rootstown, and.
authors.forename: Kristal
authors.initials: K
authors.lastname: Weber
authors.affiliation: Department of Integrative Medical Sciences, Northeast Ohio Medical University, Rootstown, and.
authors.forename: William M
authors.initials: WM
authors.lastname: Chilian
authors.affiliation: Department of Integrative Medical Sciences, Northeast Ohio Medical University, Rootstown, and Summa Cardiovascular Institute, Summa Health System, Akron, Ohio.
authors.forename: Marc S
authors.initials: MS
authors.lastname: Penn
authors.affiliation: Department of Integrative Medical Sciences, Northeast Ohio Medical University, Rootstown, and fdong@neomed.edu.
authors.forename: Feng
authors.initials: F
authors.lastname: Dong
mesh_terms: D000600:Amino Acids, Dicarboxylic / Q000494:pharmacology*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002316:Cardiotonic Agents / Q000494:pharmacology*; D015687:Cell Hypoxia; D002460:Cell Line; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000494:pharmacology; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism; D064799:Hypoxia-Inducible Factor-Proline Dioxygenases / Q000037:antagonists & inhibitors / Q000378:metabolism; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009203:Myocardial Infarction / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D009206:Myocardium / Q000378:metabolism* / Q000473:pathology; D051381:Rats; D019718:Receptors, CXCR4 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D020127:Recovery of Function; D015398:Signal Transduction / Q000187:drug effects; D013234:Stem Cells / Q000187:drug effects / Q000378:metabolism; D013318:Stroke Volume / Q000187:drug effects; D013997:Time Factors; D015854:Up-Regulation; D016277:Ventricular Function, Left / Q000187:drug effects*
chemical_list: D000600:Amino Acids, Dicarboxylic; C514936:CXCR4 protein, mouse; D002316:Cardiotonic Agents; C486264:Cxcr4 protein, rat; D004791:Enzyme Inhibitors; C497443:Hif1a protein, mouse; C497444:Hif1a protein, rat; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D019718:Receptors, CXCR4; D064799:Hypoxia-Inducible Factor-Proline Dioxygenases; C040947:oxalylglycine
keywords: hypoxia; myocardial infarction; stem cells