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409 CHANGES OF ENDOGLIN LEVELS IN SERUM AND MICE AORTA WITH RESPECT TO CHOLESTEROL AND ATORVASTATIN
79th EAS Congress
Atherosclerosis Supplements 12, no. 1 (2011) 13–184
405 RELATIONSHIPS BETWEEN MARKERS OF APOPTOSIS AND ANTIBODIES TO OXIDIZED LOW-DENSITY LIPOPROTEINS IN PROGRESSING ATHEROSCLEROSIS V. Gurevich1 , L. Vasina2 , N. Petrischev3 , A. Lugovaya4 . 1 Center of Atherosclerosis and Lipid Disorders, Mechnicov’s State Medical Academy, Saint Petersburg, 2 Lab of Microcirculation, Amasov’s Center of Heart, Blood and Endocrinology, Saint-Petersburg, 3 Chair of Pathology, 4 Pavlov’s State Medical University, Saint Petersburg, Russia The purpose of this study was to examine the relationships between soluble apoptosis markers sBcl-2 and sApo-1/Fas and antibodies to oxidized LDL in acute coronary syndrome. Methods: Blood samples of 190 patients with clinical and instrumental signs of acute coronary syndrome were examined. Antibodies to oxidized LDL, sBcl-2 and sApo-1/Fas in the blood plasma were determined by ELISA. Results: Significantly higher levels of antibodies to oxidized LDL and an increase of sApo-1/Fas and sBcl-2 in the blood plasma have been shown. In unstable angina sAro-1/Fas and sBcl-2 levels were 1980.4±112.62 pg/ml and 29.1±8.16 IU/ml, respectively, in acute myocardial infarction with non-STsegment elevation (NSTEMI) sAro-1/Fas and sBcl-2 levels were 1898.2±132.41 pg/ml and 30.5±9.28 IU/ml, respectively, while in acute myocardial infarction with ST-segment elevation sAro-1/Fas and sBcl-2 levels was 2951.0±184.41 pg/ml and 61.5±15.23 IU/ml, respectively (p < 0.05). In the control group sAro1/Fas level was 1464.0±209.28 pg/ml, sBcl-2 level was 13.7±3.15 IU/ml. The positive correlation between the antibodies to oxidized LDL and the content of sBcl-2 and sApo-1/Fas was demonstrated (r = 0.65, and r = 0.71, respectively, p < 0.05). Conclusions: The data obtained confirm the involvement of modified LDL in the development of Fas-mediated apoptosis of endothelial cells in progressing atherosclerosis. 406 THE DELETERIOUS INFLUENCE OF TENOFOVIR-BASED THERAPIES ON THE PROGRESSION OF ATHEROSCLEROSIS IN HIV-INFECTED PATIENTS 2 G. Aragones1 , P. Pardo2 , R. Beltran-Deb ´ on ´ 1 , A. Rull1 , L. Fernandez-Sender ´ , J. Joven1 , C. Alonso-Villaverde3 . 1 Centre Recerca Biomedica, 2 Servei ` de Medicina Interna, Institut Investigacio´ Sanitaria Pere Virgili, Hospital Universitari Sant Joan, Universitat Rovira i Virgili, Reus, 3 Servei de Medicina ` Interna, Hospital Son Llatzer, Palma de Mallorca, Spain Objective: To investigate the potential differential effects of antiretroviral therapies on unbalanced chemokine hemostasis and on the progression of atherosclerosis in HIV patients. Methods and Design: We conducted a two-year prospective study in a cohort of 147 HIV-infected patients. We assessed changes in the circulating levels of inflammatory biomarkers and in the progression of subclinical atherosclerosis. The expression levels of selected genes (MCP-1, CCR2, CCR5 and CXCR-4) in circulating leukocytes were also assessed at the end of the follow-up period. Results: Control subjects showed significantly lower plasma concentrations of CRP (p < 0.001), tPA (p < 0.001), IL-6 (p = 0.04) and MCP-1 (p = 0.03) than HIV-infected patients at a baseline time-point. After two years of follow-up, the observed decreases in plasma inflammatory biomarker levels were only significant for MCP-1 (p < 0.001), tPA (p = 0.001) and IL-6 (p = 0.01). A decrease in the plasma MCP-1 concentration was associated with the progression of atherosclerosis, and this effect was negligible only in patients receiving tenofovir (TDF) therapy. Multivariate analysis confirmed that treatment with TDF was positively and significantly associated with a higher likelihood of subclinical atherosclerosis progression (OR = 7.1; p = 0.002; 95% CI: 2−24). However, the expression levels of selected genes in blood cells showed associations with the viral load and plasma total and HDL-cholesterol levels. Conclusion: Current antiretroviral treatments may partially attenuate the influence of HIV infection on certain inflammatory pathways, though patients receiving TDF therapy must be carefully monitored with respect to the presence and/or progression of atherosclerosis. 407 DUFFY BLOOD ALLOANTIGEN SYSTEM INFLUENCES INFLAMMATORY CHEMOKINE CONCENTRATION IN SERUM BUT NOT PLASMA: GEOGRAPHIC DIFFERENTIATION AS AN ADDITIONAL CONFOUNDING FACTOR M. Barreda, G. Aragones, A. Rull, R. Beltran-Deb ´ on, ´ J. Camps, J. Joven. ` Centre Recerca Biomedica, Institut Investigacio´ Sanitaria Pere Virgili, Hospital Universitari Sant Joan, Universitat Rovira i Virgili, Reus, Spain Objectives: The Asp42Gly polymorphism (rs12075) in the Duffy antigen/receptor for chemokines (DARC) gene is a major determinant of chemokine binding in endothelial and red blood cells. We explored whether this genetic variant represents a confounding factor in the interpretation of monocyte chemoattractant protein-1 (MCP-1) concentration in circulating blood. Methods: Chemokines concentrations in serum and plasma were measured in 293 healthy Caucasian participants who are representative of our geographic area. The rs12075 genotype distribution was also assessed in this population.
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Results: Plasma MCP-1 concentration did not vary among the rs12075 polymorphism derived genotypes (pg/mL, AA: 178.5±56.4; AG: 190.1±75.3 and GG: 185.5±73.6). However, there were significant increases in serum MCP-1 related to the presence of the A allele (pg/mL, AA: 365.6±138.8; AG: 329.2±132.6 and GG: 262.2±73.8). We also observed a significant variation in the genotype frequency in our population with respect to other Caucasian populations, indicating the presence of an additional genetic confounding factor. Conclusions: Differences between serum and plasma MCP-1 concentrations suggest a clotting effect that is associated with the rs12075 polymorphism in DARC. These findings limit the value of circulating MCP-1 as a biomarker and apparently indicate a pathophysiological role for chemokine receptors that do not activate intracellular signaling pathways. 408 PLASMA CHEMERIN IS ASSOCIATED WITH MARKERS OF INFLAMMATION AND CORONARY ARTERY DISEASE IN PATIENTS NOT ON ASPIRIN M. Herova´ 1,2 , M. Schmid1 , M. Hersberger1,2 . 1 Division of Clinical Chemistry and Biochemistry, University Children’s Hospital Zurich, 2 Zurich Center for Integrative Human Physiology (ZIHP), Zurich, Switzerland Background: Chemerin is a peptide chemoattractant of macrophages and dendritic cells and was recently identified as an adipokine. Active chemerin is found in plasma and was shown to regulate inflammation and adipocyte differentiation. Inflammation, obesity and metabolic syndrome are pronounced risk factors for coronary artery disease (CAD). Therefore we investigated whether plasma chemerin levels are associated with inflammatory markers and atherosclerosis in a case-control study for CAD. Research design and Method: Total chemerin levels were measured by ELISA in plasma of angiographically documented CAD patients (n = 249) and healthy controls (n = 221). Results: Plasma chemerin levels were highly associated with high sensitive C-reactive protein, creatinine, BMI and hypertension and negatively associated with HDL levels. Plasma chemerin levels were similar in controls and CAD patients. However, chemerin levels were significantly higher in CAD patients not undergoing aspirin treatment than in CAD patients on aspirin treatment and in controls. Conclusion: Chemerin is strongly associated with markers of inflammation and components of the metabolic syndrome and is associated with CAD in patients not receiving anti-inflammatory treatment. This suggests that high chemerin levels are associated with inflammation accompanying CAD. 409 CHANGES OF ENDOGLIN LEVELS IN SERUM AND MICE AORTA WITH RESPECT TO CHOLESTEROL AND ATORVASTATIN L. Veˇceˇrova, ´ Z. Strasky, J. Rathouska, M. Slanarova, E. Brcakova, P. Nachtigal. Charles University, Faculty of Pharmacy, Hradec Kralove, Czech Republic Endoglin (CD 105) also known as a type III TGF-b receptor is able to modulate TGF-b1 activity suggesting its role in atherogenesis. In this study, we hypothesized, whether endoglin expression in aorta and its blood serum levels are affected by cholesterol levels and/or atorvastatin treatment. ApoE/LDLR double knockout mice were divided into 4 groups (n = 32). Mice on chow diet, mice fed with 1% cholesterol diet, mice on chow diet with atorvastatin 50 mg/kg/day and mice fed with 1% cholesterol diet with atorvastatin 50 mg/kg/day. Cholesterol levels, ELISA analysis of endoglin in blood serum and Western blot analysis of endoglin in aorta were performed. Cholesterol feeding resulted in a significant increase of cholesterol and endoglin levels in blood serum, whereas endoglin expression in aorta decreased, when compared to mice on chow diet. Atorvastatin treatment in mice on chow diet resulted in a significant increase of cholesterol levels and endoglin expression in aorta with no changes of endoglin levels in blood. Atorvastatin treatment in cholesterol fed mice resulted in a significant decrease of cholesterol and endoglin levels in blood serum, with concurrent increase of endoglin expression in aorta, when compared to untreated mice. In conclusion, changes in endoglin blood serum levels are conversely related to its expression in aorta, suggesting that endoglin might be interesting blood marker, which could reflect atherosclerotic process and/or efficiency of statin treatment. This work was supported by grant from The Grant Agency of Charles University in Prague number 129208/C and by the grant SVV-2010–261−00.
Atherosclerosis Supplements 12, no. 1 (2011) 13–184
405 RELATIONSHIPS BETWEEN MARKERS OF APOPTOSIS AND ANTIBODIES TO OXIDIZED LOW-DENSITY LIPOPROTEINS IN PROGRESSING ATHEROSCLEROSIS V. Gurevich1 , L. Vasina2 , N. Petrischev3 , A. Lugovaya4 . 1 Center of Atherosclerosis and Lipid Disorders, Mechnicov’s State Medical Academy, Saint Petersburg, 2 Lab of Microcirculation, Amasov’s Center of Heart, Blood and Endocrinology, Saint-Petersburg, 3 Chair of Pathology, 4 Pavlov’s State Medical University, Saint Petersburg, Russia The purpose of this study was to examine the relationships between soluble apoptosis markers sBcl-2 and sApo-1/Fas and antibodies to oxidized LDL in acute coronary syndrome. Methods: Blood samples of 190 patients with clinical and instrumental signs of acute coronary syndrome were examined. Antibodies to oxidized LDL, sBcl-2 and sApo-1/Fas in the blood plasma were determined by ELISA. Results: Significantly higher levels of antibodies to oxidized LDL and an increase of sApo-1/Fas and sBcl-2 in the blood plasma have been shown. In unstable angina sAro-1/Fas and sBcl-2 levels were 1980.4±112.62 pg/ml and 29.1±8.16 IU/ml, respectively, in acute myocardial infarction with non-STsegment elevation (NSTEMI) sAro-1/Fas and sBcl-2 levels were 1898.2±132.41 pg/ml and 30.5±9.28 IU/ml, respectively, while in acute myocardial infarction with ST-segment elevation sAro-1/Fas and sBcl-2 levels was 2951.0±184.41 pg/ml and 61.5±15.23 IU/ml, respectively (p < 0.05). In the control group sAro1/Fas level was 1464.0±209.28 pg/ml, sBcl-2 level was 13.7±3.15 IU/ml. The positive correlation between the antibodies to oxidized LDL and the content of sBcl-2 and sApo-1/Fas was demonstrated (r = 0.65, and r = 0.71, respectively, p < 0.05). Conclusions: The data obtained confirm the involvement of modified LDL in the development of Fas-mediated apoptosis of endothelial cells in progressing atherosclerosis. 406 THE DELETERIOUS INFLUENCE OF TENOFOVIR-BASED THERAPIES ON THE PROGRESSION OF ATHEROSCLEROSIS IN HIV-INFECTED PATIENTS 2 G. Aragones1 , P. Pardo2 , R. Beltran-Deb ´ on ´ 1 , A. Rull1 , L. Fernandez-Sender ´ , J. Joven1 , C. Alonso-Villaverde3 . 1 Centre Recerca Biomedica, 2 Servei ` de Medicina Interna, Institut Investigacio´ Sanitaria Pere Virgili, Hospital Universitari Sant Joan, Universitat Rovira i Virgili, Reus, 3 Servei de Medicina ` Interna, Hospital Son Llatzer, Palma de Mallorca, Spain Objective: To investigate the potential differential effects of antiretroviral therapies on unbalanced chemokine hemostasis and on the progression of atherosclerosis in HIV patients. Methods and Design: We conducted a two-year prospective study in a cohort of 147 HIV-infected patients. We assessed changes in the circulating levels of inflammatory biomarkers and in the progression of subclinical atherosclerosis. The expression levels of selected genes (MCP-1, CCR2, CCR5 and CXCR-4) in circulating leukocytes were also assessed at the end of the follow-up period. Results: Control subjects showed significantly lower plasma concentrations of CRP (p < 0.001), tPA (p < 0.001), IL-6 (p = 0.04) and MCP-1 (p = 0.03) than HIV-infected patients at a baseline time-point. After two years of follow-up, the observed decreases in plasma inflammatory biomarker levels were only significant for MCP-1 (p < 0.001), tPA (p = 0.001) and IL-6 (p = 0.01). A decrease in the plasma MCP-1 concentration was associated with the progression of atherosclerosis, and this effect was negligible only in patients receiving tenofovir (TDF) therapy. Multivariate analysis confirmed that treatment with TDF was positively and significantly associated with a higher likelihood of subclinical atherosclerosis progression (OR = 7.1; p = 0.002; 95% CI: 2−24). However, the expression levels of selected genes in blood cells showed associations with the viral load and plasma total and HDL-cholesterol levels. Conclusion: Current antiretroviral treatments may partially attenuate the influence of HIV infection on certain inflammatory pathways, though patients receiving TDF therapy must be carefully monitored with respect to the presence and/or progression of atherosclerosis. 407 DUFFY BLOOD ALLOANTIGEN SYSTEM INFLUENCES INFLAMMATORY CHEMOKINE CONCENTRATION IN SERUM BUT NOT PLASMA: GEOGRAPHIC DIFFERENTIATION AS AN ADDITIONAL CONFOUNDING FACTOR M. Barreda, G. Aragones, A. Rull, R. Beltran-Deb ´ on, ´ J. Camps, J. Joven. ` Centre Recerca Biomedica, Institut Investigacio´ Sanitaria Pere Virgili, Hospital Universitari Sant Joan, Universitat Rovira i Virgili, Reus, Spain Objectives: The Asp42Gly polymorphism (rs12075) in the Duffy antigen/receptor for chemokines (DARC) gene is a major determinant of chemokine binding in endothelial and red blood cells. We explored whether this genetic variant represents a confounding factor in the interpretation of monocyte chemoattractant protein-1 (MCP-1) concentration in circulating blood. Methods: Chemokines concentrations in serum and plasma were measured in 293 healthy Caucasian participants who are representative of our geographic area. The rs12075 genotype distribution was also assessed in this population.
87
Results: Plasma MCP-1 concentration did not vary among the rs12075 polymorphism derived genotypes (pg/mL, AA: 178.5±56.4; AG: 190.1±75.3 and GG: 185.5±73.6). However, there were significant increases in serum MCP-1 related to the presence of the A allele (pg/mL, AA: 365.6±138.8; AG: 329.2±132.6 and GG: 262.2±73.8). We also observed a significant variation in the genotype frequency in our population with respect to other Caucasian populations, indicating the presence of an additional genetic confounding factor. Conclusions: Differences between serum and plasma MCP-1 concentrations suggest a clotting effect that is associated with the rs12075 polymorphism in DARC. These findings limit the value of circulating MCP-1 as a biomarker and apparently indicate a pathophysiological role for chemokine receptors that do not activate intracellular signaling pathways. 408 PLASMA CHEMERIN IS ASSOCIATED WITH MARKERS OF INFLAMMATION AND CORONARY ARTERY DISEASE IN PATIENTS NOT ON ASPIRIN M. Herova´ 1,2 , M. Schmid1 , M. Hersberger1,2 . 1 Division of Clinical Chemistry and Biochemistry, University Children’s Hospital Zurich, 2 Zurich Center for Integrative Human Physiology (ZIHP), Zurich, Switzerland Background: Chemerin is a peptide chemoattractant of macrophages and dendritic cells and was recently identified as an adipokine. Active chemerin is found in plasma and was shown to regulate inflammation and adipocyte differentiation. Inflammation, obesity and metabolic syndrome are pronounced risk factors for coronary artery disease (CAD). Therefore we investigated whether plasma chemerin levels are associated with inflammatory markers and atherosclerosis in a case-control study for CAD. Research design and Method: Total chemerin levels were measured by ELISA in plasma of angiographically documented CAD patients (n = 249) and healthy controls (n = 221). Results: Plasma chemerin levels were highly associated with high sensitive C-reactive protein, creatinine, BMI and hypertension and negatively associated with HDL levels. Plasma chemerin levels were similar in controls and CAD patients. However, chemerin levels were significantly higher in CAD patients not undergoing aspirin treatment than in CAD patients on aspirin treatment and in controls. Conclusion: Chemerin is strongly associated with markers of inflammation and components of the metabolic syndrome and is associated with CAD in patients not receiving anti-inflammatory treatment. This suggests that high chemerin levels are associated with inflammation accompanying CAD. 409 CHANGES OF ENDOGLIN LEVELS IN SERUM AND MICE AORTA WITH RESPECT TO CHOLESTEROL AND ATORVASTATIN L. Veˇceˇrova, ´ Z. Strasky, J. Rathouska, M. Slanarova, E. Brcakova, P. Nachtigal. Charles University, Faculty of Pharmacy, Hradec Kralove, Czech Republic Endoglin (CD 105) also known as a type III TGF-b receptor is able to modulate TGF-b1 activity suggesting its role in atherogenesis. In this study, we hypothesized, whether endoglin expression in aorta and its blood serum levels are affected by cholesterol levels and/or atorvastatin treatment. ApoE/LDLR double knockout mice were divided into 4 groups (n = 32). Mice on chow diet, mice fed with 1% cholesterol diet, mice on chow diet with atorvastatin 50 mg/kg/day and mice fed with 1% cholesterol diet with atorvastatin 50 mg/kg/day. Cholesterol levels, ELISA analysis of endoglin in blood serum and Western blot analysis of endoglin in aorta were performed. Cholesterol feeding resulted in a significant increase of cholesterol and endoglin levels in blood serum, whereas endoglin expression in aorta decreased, when compared to mice on chow diet. Atorvastatin treatment in mice on chow diet resulted in a significant increase of cholesterol levels and endoglin expression in aorta with no changes of endoglin levels in blood. Atorvastatin treatment in cholesterol fed mice resulted in a significant decrease of cholesterol and endoglin levels in blood serum, with concurrent increase of endoglin expression in aorta, when compared to untreated mice. In conclusion, changes in endoglin blood serum levels are conversely related to its expression in aorta, suggesting that endoglin might be interesting blood marker, which could reflect atherosclerotic process and/or efficiency of statin treatment. This work was supported by grant from The Grant Agency of Charles University in Prague number 129208/C and by the grant SVV-2010–261−00.