title: Double-edged role of the CXCL12/CXCR4 axis in experimental myocardial infarction.
abstract: OBJECTIVE
  Here we assess the intrinsic functions of the chemokine receptor CXCR4 in remodeling after myocardial infarction (MI) using Cxcr4 heterozygous (Cxcr4(+/-)) mice.
  
  
  BACKGROUND
  Myocardial necrosis triggers complex remodeling and inflammatory changes. The chemokine CXCL12 has been implicated in protection and therapeutic regeneration after MI through recruiting angiogenic outgrowth cells, improving neovascularization and cardiac function, but the endogenous role of its receptor CXCR4 is unknown.
  
  
  METHODS
  MI was induced by ligation of the left descending artery. Langendoff perfusion, echocardiography, quantitative immunohistochemistry, flow cytometry, angiogenesis assays, and cardiomyocyte analysis were performed.
  
  
  RESULTS
  After 4 weeks, infarct size was reduced in Cxcr4(+/-) mice compared with wild-type mice and in respective bone marrow chimeras compared with controls. This was associated with altered inflammatory cell recruitment, decreased neutrophil content, delayed monocyte infiltration, and a predominance of Gr1(low) over classic Gr1(high) monocytes. Basal coronary flow and its recovery after MI were impaired in Cxcr4(+/-)mice, paralleled by reduced angiogenesis, myocardial vessel density, and endothelial cell count. Notably, no differences in cardiac function were seen in Cxcr4(+/-)mice compared with wild-type mice. Despite defective angiogenesis, Cxcr4(+/-) mouse hearts showed no difference in CXCL12, vascular endothelial growth factor or apoptosis-related gene expression. Electron microscopy revealed lipofuscin-like lipid accumulation in Cxcr4(+/-) mouse hearts and analysis of lipid extracts detected high levels of phosphatidylserine, which protect cardiomyocytes from hypoxic stress in vitro.
  
  
  CONCLUSIONS
  CXCR4 plays a crucial role in endogenous remodeling processes after MI, contributing to inflammatory/progenitor cell recruitment and neovascularization, whereas its deficiency limits infarct size and causes adaptation to hypoxic stress. This should be carefully scrutinized when devising therapeutic strategies involving the CXCL12/CXCR4 axis.
authors: Institute for Molecular Cardiovascular Research, RWTH Aachen University, Aachen, Germany.
authors: Elisa A
authors: EA
authors: Liehn
authors: Nancy
authors: N
authors: Tuchscheerer
authors: Isabella
authors: I
authors: Kanzler
authors: Maik
authors: M
authors: Drechsler
authors: Line
authors: L
authors: Fraemohs
authors: Alexander
authors: A
authors: Schuh
authors: Rory R
authors: RR
authors: Koenen
authors: Simone
authors: S
authors: Zander
authors: Oliver
authors: O
authors: Soehnlein
authors: Mihail
authors: M
authors: Hristov
authors: Gabriela
authors: G
authors: Grigorescu
authors: Andreea O
authors: AO
authors: Urs
authors: Mircea
authors: M
authors: Leabu
authors: Ilie
authors: I
authors: Bucur
authors: Marc W
authors: MW
authors: Merx
authors: Alma
authors: A
authors: Zernecke
authors: Josef
authors: J
authors: Ehling
authors: Felix
authors: F
authors: Gremse
authors: Twan
authors: T
authors: Lammers
authors: Fabian
authors: F
authors: Kiessling
authors: Jürgen
authors: J
authors: Bernhagen
authors: Andreas
authors: A
authors: Schober
authors: Christian
authors: C
authors: Weber
mesh_terms: D000818:Animals; D017209:Apoptosis; D054377:Chemokine CXCL12 / Q000096:biosynthesis / Q000235:genetics*; D004247:DNA / Q000235:genetics*; D004195:Disease Models, Animal; D005786:Gene Expression Regulation; D051379:Mice; D008810:Mice, Inbred C57BL; D008854:Microscopy, Electron; D009203:Myocardial Infarction / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D032383:Myocytes, Cardiac / Q000378:metabolism / Q000648:ultrastructure; D019718:Receptors, CXCR4 / Q000096:biosynthesis / Q000235:genetics*; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: C514936:CXCR4 protein, mouse; D054377:Chemokine CXCL12; D019718:Receptors, CXCR4; D004247:DNA