- Email: [email protected]
Inflammation and metabolism: The role of chemokine (C-C MOTIF) LIGAND 2
Abstracts / Atherosclerosis 241 (2015) e32ee71
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promotion and extracellular matrix remodelling. Last but not least, we found the macrophage-like phenotype in intimal SMC and the pro-inflammatory capacity is associated with the elevated level of key transcription factors STAT1a, IRF8, IRF9, KLF4 and HIF2a. In conclusion, we propose a critical role of intimal SMC with innate immune capacity in the development of atherosclerosis. Targeting the phenotypic modulation of intimal SMC might be a new strategy for further clinical treatment.
EAS-0372. INFLAMMATION AND METABOLISM: THE ROLE OF CHEMOKINE (C-C MOTIF) LIGAND 2 -Casado , M. Guirro, A. Herna ndezE. Rodríguez-Gallego, R. Marine , S. Fern Aguilera, F. Luciano-Mateo, N. Cabre andez-Arroyo, J. Camps, J. Joven. Unitat de Recerca Biom edica (URB-CRB), Institut d'Investigacio ria Pere Virgili (IISPV) Universitat Rovira i Virgili (URV), Reus, Spain Sanita Aim: Low-grade chronic inflammation is a consequence of a compromised management of excessive energy intake and represents a significant factor in the development of some non-communicable diseases, such as obesity an atherosclerosis. Chemokines and their receptors associate immune system and metabolism. These molecules play a crucial role in the inflammatory process and participate in the course of some pathologies through the recruitment of macrophages to metabolically compromised tissues. The aim of this study was to determine the effects of a continuous and ubiquitous secretion of CCL2, a proinflamatory chemokine, in a situation of energy surplus and the consequences of CCR2 (CCL2 receptor) absence on these effects. Methods: We carried out a study using a transgenic mouse which overexpresses CCL2, a transgenic mouse with an overexpression of CCL2 without CCR2 and three controls (wild type, CCL2 knock-out and CCR2 knock-out), all of them fed with a standard or high fat diet during six weeks. Results: An overexpression of CCL2 combined with an excessive energy intake, contributes to a further development of obesity, liver steatosis and mitochondrial dysfunction, induced by an alteration in energy and lipid metabolism. Moreover, the absence of CCR2 in an inflammatory context has a protective effect, preventing the development of these pathologies. Conclusion: It has been shown a clear relationship between CCL2 action and the development of metabolic disturbances in a high fat feeding situation. Moreover, the protective effect of CCR2 absence gives useful information in the designing of new mechanism-based therapeutic strategies, such as CCR2 antagonists.
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EAS-0399. ANTI-APOLIPOPROTEIN A1 AUTOANTIBODIES INDUCE TISSUE FACTOR ACTIVITY AND EXPRESSION: A ROLE IN ATHEROTHROMBOSIS S. Pagano 1, N. Satta 1, J. Virzi 1, T. Mannic 1, P. Roux-Lombard 2, F. Mach 3, F. Montecucco 4, N. Vuilleumier 1. 1 Division of Laboratory Medicine/Human Protein science dept, Geneva University Hospital, Geneva, Switzerland; 2 Division Immunology and Allergy, Geneva University Hospital, Geneva, Switzerland; 3 Division of Cardiology, Geneva University Hospital, Geneva, Switzerland; 4 Division of Cardiology/Human Protein Science Departement, Geneva University Hospital, Geneva, Switzerland Introduction: Autoimmune-mediated inflammation plays a role inatherosclerosis and atherothrombosis, essential features for cardiovasculardisease (CVD) manifestations. Anti-Apolipoprotein A-1(ApoA1) IgG are anindependent predictor of poor cardiovascular outcome in different clinical settings,promote inflammation and atherogenesis, are associated withincreased atherosclerotic plaque vulnerability in humans and mice. Aim: to determine whether anti-ApoA-1IgG are associated withTissue Factor (TF) expression, a key coagulation pathway regulator, involved inatherothrombosis, responsible for the majority of acute CVD manifestations. Methods: atherothrombosisfeatures were explored by immunohistochemical TF staining on human carotidplaques (n¼102) from severe carotid stenosis patients.On human-monocytes-derivedmacrophages(HMDM), TF expression and activitywere detected by cytofluorimetry and chromogenic assay respectively. ApolipoproteinE knockout (ApoE-/-) mice wereintravenously infused with polyclonal antiApoA-1IgG, control isotype every twoweeks for 16weeks. Results: atheroscleroticbiopsies derived from patients with high levels of anti-ApoA-1IgG (n¼20)displayed higher TF expression when compared to biopsies from patients with lowantibodies titers (9.3%vs3.3%, p<0.0001), Spearman correlation shows asignificant association between the circulating anti-ApoA1-IgG and TFexpression (r¼0.41p<0.001), as well as between CD68 plaque expression and TFexpression (r¼0.33p¼0.004). On HMDM, anti-ApoA-1IgG induced a significant dose-dependentincrease in TF expression and pro-coagulant-activity only in supernatants andcells treated with anti-ApoA-1IgG (p¼0.02p<0.0001, p¼0.0006 respectively).Anti-ApoA-1IgG infused ApoE-/-mice show higher intraplaque TF compare to thecontrol ApoE-/-mice (p¼0.02) Conclusions: We demonstrated invivo that anti-ApoA-1IgG are associated with higher propensity to atherothrombosis, in vitro results suggest they could per se induce TF expression, supporting a possible causal link betweenanti-ApoA-1IgG and atherothrombosis.
EAS-0719. MONOCYTES SUBSETS DIFFERENTIALLY MODULATE INFLAMMATORY RESPONSES OF ENDOTHELIAL CELLS
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M. Chimen, C.M. Yates, G.B. Nash, G.E. Rainger. School of Clinical and Experimental Medicine, University of Birmingham, Birmingham, United Kingdom
e63
promotion and extracellular matrix remodelling. Last but not least, we found the macrophage-like phenotype in intimal SMC and the pro-inflammatory capacity is associated with the elevated level of key transcription factors STAT1a, IRF8, IRF9, KLF4 and HIF2a. In conclusion, we propose a critical role of intimal SMC with innate immune capacity in the development of atherosclerosis. Targeting the phenotypic modulation of intimal SMC might be a new strategy for further clinical treatment.
EAS-0372. INFLAMMATION AND METABOLISM: THE ROLE OF CHEMOKINE (C-C MOTIF) LIGAND 2 -Casado , M. Guirro, A. Herna ndezE. Rodríguez-Gallego, R. Marine , S. Fern Aguilera, F. Luciano-Mateo, N. Cabre andez-Arroyo, J. Camps, J. Joven. Unitat de Recerca Biom edica (URB-CRB), Institut d'Investigacio ria Pere Virgili (IISPV) Universitat Rovira i Virgili (URV), Reus, Spain Sanita Aim: Low-grade chronic inflammation is a consequence of a compromised management of excessive energy intake and represents a significant factor in the development of some non-communicable diseases, such as obesity an atherosclerosis. Chemokines and their receptors associate immune system and metabolism. These molecules play a crucial role in the inflammatory process and participate in the course of some pathologies through the recruitment of macrophages to metabolically compromised tissues. The aim of this study was to determine the effects of a continuous and ubiquitous secretion of CCL2, a proinflamatory chemokine, in a situation of energy surplus and the consequences of CCR2 (CCL2 receptor) absence on these effects. Methods: We carried out a study using a transgenic mouse which overexpresses CCL2, a transgenic mouse with an overexpression of CCL2 without CCR2 and three controls (wild type, CCL2 knock-out and CCR2 knock-out), all of them fed with a standard or high fat diet during six weeks. Results: An overexpression of CCL2 combined with an excessive energy intake, contributes to a further development of obesity, liver steatosis and mitochondrial dysfunction, induced by an alteration in energy and lipid metabolism. Moreover, the absence of CCR2 in an inflammatory context has a protective effect, preventing the development of these pathologies. Conclusion: It has been shown a clear relationship between CCL2 action and the development of metabolic disturbances in a high fat feeding situation. Moreover, the protective effect of CCR2 absence gives useful information in the designing of new mechanism-based therapeutic strategies, such as CCR2 antagonists.
Ă
Ă
EAS-0399. ANTI-APOLIPOPROTEIN A1 AUTOANTIBODIES INDUCE TISSUE FACTOR ACTIVITY AND EXPRESSION: A ROLE IN ATHEROTHROMBOSIS S. Pagano 1, N. Satta 1, J. Virzi 1, T. Mannic 1, P. Roux-Lombard 2, F. Mach 3, F. Montecucco 4, N. Vuilleumier 1. 1 Division of Laboratory Medicine/Human Protein science dept, Geneva University Hospital, Geneva, Switzerland; 2 Division Immunology and Allergy, Geneva University Hospital, Geneva, Switzerland; 3 Division of Cardiology, Geneva University Hospital, Geneva, Switzerland; 4 Division of Cardiology/Human Protein Science Departement, Geneva University Hospital, Geneva, Switzerland Introduction: Autoimmune-mediated inflammation plays a role inatherosclerosis and atherothrombosis, essential features for cardiovasculardisease (CVD) manifestations. Anti-Apolipoprotein A-1(ApoA1) IgG are anindependent predictor of poor cardiovascular outcome in different clinical settings,promote inflammation and atherogenesis, are associated withincreased atherosclerotic plaque vulnerability in humans and mice. Aim: to determine whether anti-ApoA-1IgG are associated withTissue Factor (TF) expression, a key coagulation pathway regulator, involved inatherothrombosis, responsible for the majority of acute CVD manifestations. Methods: atherothrombosisfeatures were explored by immunohistochemical TF staining on human carotidplaques (n¼102) from severe carotid stenosis patients.On human-monocytes-derivedmacrophages(HMDM), TF expression and activitywere detected by cytofluorimetry and chromogenic assay respectively. ApolipoproteinE knockout (ApoE-/-) mice wereintravenously infused with polyclonal antiApoA-1IgG, control isotype every twoweeks for 16weeks. Results: atheroscleroticbiopsies derived from patients with high levels of anti-ApoA-1IgG (n¼20)displayed higher TF expression when compared to biopsies from patients with lowantibodies titers (9.3%vs3.3%, p<0.0001), Spearman correlation shows asignificant association between the circulating anti-ApoA1-IgG and TFexpression (r¼0.41p<0.001), as well as between CD68 plaque expression and TFexpression (r¼0.33p¼0.004). On HMDM, anti-ApoA-1IgG induced a significant dose-dependentincrease in TF expression and pro-coagulant-activity only in supernatants andcells treated with anti-ApoA-1IgG (p¼0.02p<0.0001, p¼0.0006 respectively).Anti-ApoA-1IgG infused ApoE-/-mice show higher intraplaque TF compare to thecontrol ApoE-/-mice (p¼0.02) Conclusions: We demonstrated invivo that anti-ApoA-1IgG are associated with higher propensity to atherothrombosis, in vitro results suggest they could per se induce TF expression, supporting a possible causal link betweenanti-ApoA-1IgG and atherothrombosis.
EAS-0719. MONOCYTES SUBSETS DIFFERENTIALLY MODULATE INFLAMMATORY RESPONSES OF ENDOTHELIAL CELLS
Ă
M. Chimen, C.M. Yates, G.B. Nash, G.E. Rainger. School of Clinical and Experimental Medicine, University of Birmingham, Birmingham, United Kingdom