Cxcr4 deficiency in mice reduced infarct size and caused adaptation to hypoxic stress after myocardial infarction, despite impairing angiogenesis and coronary flow recovery.
Does CXCR4 deficiency alter infarct size and remodeling after myocardial infarction in mice?
CXCR4 deficiency limits infarct size and alters inflammatory cell recruitment after myocardial infarction in mice, despite impairing angiogenesis.
Objectives Here we assess the intrinsic functions of the chemokine receptor CXCR4 in remodeling after myocardial infarction (MI) using Cxcr4 heterozygous (Cxcr(4+/-)) 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. (J Am Coll Cardiol 2011;58:2415-23) Original language English Pages (from-to) 2415-2423 Number of pages 9 Journal Journal of the American College of Cardiology Volume 58 Issue number 23 DOIs https://doi.org/10.1016/j.jacc.2011.08.033 Publication status Published - 29 Nov 2011 Keywords angiogenesis chemokine receptor inflammation myocardial infarction myocardial remodeling
“The precise physiological functions of the chemokine and its receptor are poorly understood, although these are the crucial determinants of their therapeutic potential and of possible side-effects. We therefore studied the effects of infarction in an animal model in which the amount of CXCR4 produced is specifically reduced. We focused on the molecular and cellular consequences of infarction, particularly with respect to the recovery of cardiac function, formation of scar tissue, severity of inflammation, and neovascularization of heart muscle.”
Liehn et al. (Tue,) conducted a other in Myocardial infarction. Cxcr4 heterozygosity (Cxcr4+/-) vs. Wild-type mice was evaluated on Infarct size and remodeling processes. Cxcr4 deficiency in mice reduced infarct size and caused adaptation to hypoxic stress after myocardial infarction, despite impairing angiogenesis and coronary flow recovery.