Ilze Bot1, Isabelle T M N Daissormont2, Alma Zernecke3, Gijs H M van Puijvelde4, Birgit Kramp5, Saskia C A de Jager4, Judith C Sluimer2, Marco Manca2, Veronica Hérias2, Marijke M Westra4, Martine Bot4, Peter J van Santbrink4, Theo J C van Berkel4, Lishan Su6, Mona Skjelland7, Lars Gullestad8, Johan Kuiper4, Bente Halvorsen9, Paul Aukrust9, Rory R Koenen5, Christian Weber5, Erik A L Biessen10. 1. Division of Biopharmaceutics, Leiden Academic Centre for Drug Research, Leiden University, Leiden, The Netherlands. Electronic address: i.bot@lacdr.leidenuniv.nl. 2. Experimental Vascular Pathology Group, Cardiovascular Research Institute Maastricht, University of Maastricht, Maastricht, The Netherlands. 3. Rudolf-Virchow-Center/DFG-Research Center for Experimental Biomedicine, University of Würzburg, Würzburg, Germany. 4. Division of Biopharmaceutics, Leiden Academic Centre for Drug Research, Leiden University, Leiden, The Netherlands. 5. Institute for Cardiovascular Prevention, Ludwig-Maximilians-Universität München, Munich, Germany. 6. Department of Microbiology & Immunology, Lineberger Comprehensive Cancer Center, Curriculum in Genetics and Molecular Biology School of Medicine, The University of North Carolina, Chapel Hill, NC 27599-7295. 7. Department of Neurology, Rikshospitalet University Hospital, University of Oslo, Norway. 8. Department of Cardiology, Rikshospitalet University Hospital, University of Oslo, Norway. 9. Department of Internal Medicine, Rikshospitalet University Hospital, University of Oslo, Norway. 10. Division of Biopharmaceutics, Leiden Academic Centre for Drug Research, Leiden University, Leiden, The Netherlands; Experimental Vascular Pathology Group, Cardiovascular Research Institute Maastricht, University of Maastricht, Maastricht, The Netherlands.
Abstract
AIMS: The SDF-1α/CXCR4 dyad was previously shown by us and others to be instrumental in intimal hyperplasia as well as early stage atherosclerosis. We here sought to investigate its impact on clinically relevant stages of atherosclerosis in mouse and man. METHODS AND RESULTS: Immunohistochemical analysis of CXCR4 expression in human atherosclerotic lesions revealed a progressive accumulation of CXCR4(+) cells during plaque progression. To address causal involvement of CXCR4 in advanced stages of atherosclerosis we reconstituted LDLr(-/-) mice with autologous bone marrow infected with lentivirus encoding SDF-1α antagonist or CXCR4 degrakine, which effects proteasomal degradation of CXCR4. Functional CXCR4 blockade led to progressive plaque expansion with disease progression, while also promoting intraplaque haemorrhage. Moreover, CXCR4 knockdown was seen to augment endothelial adhesion of neutrophils. Concordant with this finding, inhibition of CXCR4 function increased adhesive capacity and reduced apoptosis of neutrophils and resulted in hyperactivation of circulating neutrophils. Compatible with a role of the neutrophil CXCR4 in end-stage atherosclerosis, CXCR4 expression by circulating neutrophils was lowered in patients with acute cardiovascular syndromes. CONCLUSION: In conclusion, CXCR4 contributes to later stages of plaque progression by perturbing neutrophil function.
AIMS: The SDF-1α/CXCR4 dyad was previously shown by us and others to be instrumental in intimal hyperplasia as well as early stage atherosclerosis. We here sought to investigate its impact on clinically relevant stages of atherosclerosis in mouse and man. METHODS AND RESULTS: Immunohistochemical analysis of CXCR4 expression in humanatherosclerotic lesions revealed a progressive accumulation of CXCR4(+) cells during plaque progression. To address causal involvement of CXCR4 in advanced stages of atherosclerosis we reconstituted LDLr(-/-) mice with autologous bone marrow infected with lentivirus encoding SDF-1α antagonist or CXCR4 degrakine, which effects proteasomal degradation of CXCR4. Functional CXCR4 blockade led to progressive plaque expansion with disease progression, while also promoting intraplaque haemorrhage. Moreover, CXCR4 knockdown was seen to augment endothelial adhesion of neutrophils. Concordant with this finding, inhibition of CXCR4 function increased adhesive capacity and reduced apoptosis of neutrophils and resulted in hyperactivation of circulating neutrophils. Compatible with a role of the neutrophil CXCR4 in end-stage atherosclerosis, CXCR4 expression by circulating neutrophils was lowered in patients with acute cardiovascular syndromes. CONCLUSION: In conclusion, CXCR4 contributes to later stages of plaque progression by perturbing neutrophil function.
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