Double-Edged Role of the CXCL12/CXCR4 Axis in Experimental Myocardial Infarction

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 i...

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Published in:	Journal of the American College of Cardiology 2011-11, Vol.58 (23), p.2415-2423
Main Authors:	Liehn, Elisa A., MD, PhD, Tuchscheerer, Nancy, BS, Kanzler, Isabella, BS, Drechsler, Maik, BS, Fraemohs, Line, PhD, Schuh, Alexander, MD, Koenen, Rory R., PhD, Zander, Simone, BS, Soehnlein, Oliver, MD, PhD, Hristov, Mihail, MD, Grigorescu, Gabriela, BS, Urs, Andreea O., MS, Leabu, Mircea, PhD, Bucur, Ilie, PhD, Merx, Marc W., MD, Zernecke, Alma, MD, Ehling, Josef, MD, Gremse, Felix, BSc, Lammers, Twan, PhD, Kiessling, Fabian, MD, Bernhagen, Jürgen, PhD, Schober, Andreas, MD, Weber, Christian, MD
Format:	Article
Language:	eng
Subjects:	angiogenesis Animals Apoptosis Biological and medical sciences Bone marrow Cardiology. Vascular system Cardiovascular Chemokine CXCL12 - biosynthesis Chemokine CXCL12 - genetics chemokine receptor Coronary heart disease Disease Models, Animal DNA - genetics Gene Expression Regulation Heart Heart attacks inflammation Internal Medicine Kinases Medical sciences Mice Mice, Inbred C57BL Microscopy, Electron myocardial infarction Myocardial Infarction - genetics Myocardial Infarction - metabolism Myocardial Infarction - pathology myocardial remodeling Myocarditis. Cardiomyopathies Myocytes, Cardiac - metabolism Myocytes, Cardiac - ultrastructure Receptors, CXCR4 - biosynthesis Receptors, CXCR4 - genetics Reverse Transcriptase Polymerase Chain Reaction Rodents
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Summary:	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 Gr1low over classic Gr1high 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.
ISSN:	0735-1097 1558-3597