TY - JOUR
T1 - Double-edged role of the CXCL12/CXCR4 axis in experimental myocardial infarction
AU - Liehn, Elisa A.
AU - Tuchscheerer, Nancy
AU - Kanzler, Isabella
AU - Drechsler, Maik
AU - Fraemohs, Line
AU - Schuh, Alexander
AU - Koenen, Rory R.
AU - Zander, Simone
AU - Soehnlein, Oliver
AU - Hristov, Mihail
AU - Grigorescu, Gabriela
AU - Urs, Andreea O.
AU - Leabu, Mircea
AU - Bucur, Ilie
AU - Merx, Marc W.
AU - Zernecke, Alma
AU - Ehling, Josef
AU - Gremse, Felix
AU - Lammers, Twan
AU - Kiessling, Fabian
AU - Bernhagen, Jrgen
AU - Schober, Andreas
AU - Weber, Christian
N1 - Funding Information:
This study was supported by the Deutsche Forschungsgemeinschaft (FOR809, IRTG 1508 EuCAR) and IZKF (NTV 113-c, TV113-d) within the faculty of Medicine at RWTH Aachen University.
PY - 2011/11/29
Y1 - 2011/11/29
N2 - Objectives: 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 Cxcr4mice, paralleled by reduced angiogenesis, myocardial vessel density, and endothelial cell count. Notably, no differences in cardiac function were seen in Cxcr4mice 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.
AB - Objectives: 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 Cxcr4mice, paralleled by reduced angiogenesis, myocardial vessel density, and endothelial cell count. Notably, no differences in cardiac function were seen in Cxcr4mice 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.
KW - angiogenesis
KW - chemokine receptor
KW - inflammation
KW - myocardial infarction
KW - myocardial remodeling
U2 - 10.1016/j.jacc.2011.08.033
DO - 10.1016/j.jacc.2011.08.033
M3 - Journal article
C2 - 22115649
AN - SCOPUS:81855225283
SN - 0735-1097
VL - 58
SP - 2415
EP - 2423
JO - Journal of the American College of Cardiology
JF - Journal of the American College of Cardiology
IS - 23
ER -