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Background Chemokines and neutrophils, known as important players in the inflammatory cascade, also contribute to heart tissue recovery and scar formation after myocardial infarction (MI). The objective of this study was to determine the importance of ELR-containing CXC chemokine KC in neutrophil infiltration and neoangiogenesis, in a mouse model of chronic MI. Methods and results MI was induced in mice divided in four groups: control (untreated), anti-KC “later” (anti-KC antibody injections started 4 days after MI and then delivered every 72 hours for 3 weeks, to inhibit angiogenesis), anti-KC “earlier” (anti-KC antibody injections 1 day before and 1 day after MI, to block neutrophil infiltration), anti-KC (anti-KC antibody injections 1 day before and 1 day after MI, and then every 72 hours for 3 weeks). The efficiency of the anti-KC treatment was determined by the measurement of KC serum concentration and immunofluorescence staining, in each of the four groups. Surprisingly, we did not find any difference in neutrophil infiltration in the infarcted area between untreated and treated animals. Moreover, the heart function, infarct size, and neoangiogenesis were not different between the four groups. As expected, a comparable anti-CXCR2 treatment of mice before and after MI was able to significantly reduce neutrophil infiltration into the infarcted area and angiogenesis, but also to reduce the infarction size after long or “later” treatment. Conclusions The major finding of our study is that KC, a potent neutrophil chemoattractant and an established angiogenic factor, failed to interfere in the post-infarction inflammatory response, in wound healing and scar formation after MI. Therefore, these aspects need to be carefully taken into account when devising therapeutic strategies for myocardial infarction and ischemic cardiomyopathy.

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)