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WO11-OR-3 ATHEROSCLEROSIS IN APOLIPOPROTEIN E DEFICIENT MICE IS ACCELERATED BY INFLAMMATORY ADIPOSE TISSUE
Workshops WO11 Obesity and visceral fat as a risk factor of cardiovascular diseases
WO10-OR-6
COMBINED DELETION OF SR-BI AND ABCA1 IN MACROPHAGES DRAMATICALLY ENHANCES MACROPHAGE FOAM CELL FORMATION AND ATHEROSCLEROTIC LESION DEVELOPMENT
M. Pennings 1 , R.B. Hildebrand 1 , G. Chimini 2 , T.J. Van Berkel 1 , M. Van Eck 1 . 1 Division of Biopharmaceutics, Leiden/Amsterdam Center for Drug Research, Leiden University, Leiden, The Netherlands; 2 Centre D Immunologie de Marseille Luminy, INSERM, CNRS, Universite de La Mediterranee, Marseille, France ABCA1 mediates the efflux of cholesterol from macrophage foam cells to lipid-poor apoAI, while SR-BI promotes efflux to mature HDL. The aim of this study was to get further insight into a putative synergistic role of ABCA1 and SR-BI in foam cell formation and atherosclerotic lesion development in vivo. ABCA1-deficient mice were cross-bred with SR-BI-deficient mice and bone marrow transplantation experiments were performed to LDL receptor knockout (LDLr KO) mice using ABCA1xSR-BI double knockouts as donors. To induce atherosclerosis, the mice were challenged with a Western-type diet containing 0.25% cholesterol and 15% fat for 9 weeks. Serum cholesterol levels were only 863±118 mg/dL in ABCA1xSR-BI double knockout transplanted animals, as compared to 1390±98 mg/dL (p<0.01) for single ABCA1 KO, 1600±13 mg/dL (p<0.001) for single SR-BI KO, and 1610±75 mg/dL (p<0.001) for control transplanted animals. Thus, combined deletion of SR-BI and ABCA1 in macrophages resulted in ∼1.8-fold lower serum cholesterol levels. Despite the lower serum cholesterol levels, LDLr KO mice reconstituted with ABCA1xSR-BI double KO bone marrow showed more extreme foam cell formation in macrophages isolated from the peritoneal cavity. Furthermore, atherosclerotic lesion development was more extensive in the LDLr KO mice reconstituted with ABCA1xSR-BI double KO bone marrow (724±51x10E3 μm2 ) as compared to single ABCA1 KO (469±53x10E3 μm2 , P<0.001), SR-BI KO (529±30x10E3 μm2 , P<0.01), and wildtype (307±32x10E3 μm2 , P<0.001) reconstituted animals. In conclusion, combined deletion of macrophage SR-BI and ABCA1 identifies the essential independent function of ABCA1 and SR-BI in cholesterol efflux from macrophages and atherosclerotic lesion development.
WO11 OBESITY AND VISCERAL FAT AS A RISK FACTOR OF CARDIOVASCULAR DISEASES WO11-OR-3
ATHEROSCLEROSIS IN APOLIPOPROTEIN E DEFICIENT MICE IS ACCELERATED BY INFLAMMATORY ADIPOSE TISSUE
Methods: A model of inflammatory fat was produced by transplantation of visceral adipose tissue. To establish feasibility of fat depot transplantation, epididymal fat pads were harvested from WT mice and initially transplanted to ob/ob mice (n=5) deficient in leptin. WT fat transplantation produced physiologic leptin levels, prevented obesity, and restored fertility in ob/ob mice. However, the transplanted fat depots were associated with increased macrophage infiltration compared to endogenous fat (38.86±5.08 vs. 4.97±0.68% of total number of cells, p=0.00013). To determine if this inflammatory adipose depot could affect vascular disease in mice, epididymal fat depots were transplanted to atherosclerotic-prone mice deficient in apolipoprotein E (ApoEKO) (n=6) and compared to a control group of ApoEKO mice that underwent sham operation (n=6). Both groups were fed normal chow for 37 weeks. Results: There was no difference in total cholesterol or in body weight between the groups. However, ApoEKO mice transplanted with visceral fat had increased leptin (0.32±0.07 vs. 1.06±0.28 ng/ml, p=0.022), resistin (1.45±0.17 vs. 1.89±0.14 ng/ml, p=0.039), MCP-1 (278.75±37.25 vs. 494.64±49.81 pg/ml, p=0.003) and adiponectin (47.53±2.74 vs. 63.59±5.05 mg/ml, p=0.012) compared to control group. Furthermore, there was a 40% increase in the atherosclerotic surface area in the fat transplanted group (16.42±1.65 vs. 27.50±4.31%, p=0.025). Conclusion: Increased adipose tissue-related inflammation leads to increased atherosclerosis in mice. WO11-OR-4
ABDOMINAL OBESITY IS RELATED WITH CHANGES IN VASCULAR REACTIVITY OF HUMAN INTERNAL MAMMARY ARTERY INDEPENDENTLY OF OTHER CARDIOVASCULAR RISK FACTORS
C.F. Rueda-Clausen 1 , I.C. Bolivar 1 , J. Calderon 2 , M.S. Fernandez-Alfonso 3 , M. Carreno 2 , V. Cachofeiro 4 , M.P. Oubina 4 , P. Lopez-Jaramillo 1 , V. Lahera 4 . 1 Grupo Via L-Arginina Oxido Nitrico VILANO. Fundacion Cardiovascular de Colombia, Bucaramanga, Colombia; 2 Grupo de Cirugia Cardiovascular QUIRON, Fundacion Cardiovascular de Colombia, Bucaramanga, Colombia; 3 Instituto Pluridisciplinar, Universidad Complutense de Madrid, Madrid, Spain; 4 Laboratorio de Fisiopatologia Cardiovascular, Facultad de Medicina, Universidad Complutense de Madrid, Madrid, Spain A growing body of evidence suggests that abdominal obesity(AO) may play a direct role in initiating atherosclerosis as fat cells are capable of affecting endothelial function through a variety of mechanisms. The aim of this study is to evaluate changes of in-vitro vascular reactivity related with AO (waist circumference ≥80cm for women or ≥90cm for men) in subjects who underwent coronary artery bypass graft. Subjects without AO (Thin n=17) and sex and age-matched subjects with AO (Obese, n=17) were included in the analysis. Complete medical examination and determinations of glucose, lipid profile, C reactive protein, interleukin 6, interleukin 1β, tumor necrosis factor-α, p-selectin, vascular cell adhesion molecule and leptin were performed. Except for weight, body mass index and waist circumference, no significant differences were observed in other anthropometrical, hemodynamic or metabolic variables between obese and thin subjects. Only plasma leptin levels were higher in obese subjects (6.21±3.34 vs.18.1±13.48 ng/mL, p=0.04) correlating with BMI. Segments of the left internal mammary artery (IMA) were obtained to perform in-vitro vascular reactivity protocols. Relaxations to acetylcholine (10E-10 to 10E-5M)) and to sodium nitroprusside (10E-10 to 10E-5M) were significantly reduced in IMA from obese subjects. Contractile responses to angiotensin II (10E-10 to 10E-6M) were significantly higher in IMA from obese subjects. These results suggest that independently of other cardiovascular risk factors, the presence of abdominal obesity is related with both i) endothelial dysfunction and ii) changes in endothelial-independent relaxations, suggesting changes in vascular structure. Acknowledgment to Sociedad Española de Hipertensión (SHE-LELHA).
M.K. Ohman, Y. Shen, C.I. Obimba, D.T. Eitzman. Department of Internal Medicine, Division of Cardiology, University of Michigan, Ann Arbor, MI, USA Background: Accumulation of visceral adipose tissue is associated with fat leukocyte infiltration. Adipose tissue inflammation may play an important role in vascular complications associated with obesity. 76th Congress of the European Atherosclerosis Society, June 10–13, 2007, Helsinki, Finland
WORKSHOPS
FFA (p=0.003)] and LDL [0.50 μmol/L FFA (p=0.002)]. There were also significant differences between the groups in lipoprotein composition (table). Conclusion: VLDL and LDL from T2DM-MetS women were more susceptible to sPLA2-V lipolysis than those from controls, indicating a higher release of inflammatory mediators and more atherogenic lipoproteins in women with T2DM and MetS in vivo. The differences in lipoprotein composition could affect the susceptibility to sPLA2-V lipolysis by changing the micro environment of the lipoprotein phospholipid surface.
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WO10-OR-6
COMBINED DELETION OF SR-BI AND ABCA1 IN MACROPHAGES DRAMATICALLY ENHANCES MACROPHAGE FOAM CELL FORMATION AND ATHEROSCLEROTIC LESION DEVELOPMENT
M. Pennings 1 , R.B. Hildebrand 1 , G. Chimini 2 , T.J. Van Berkel 1 , M. Van Eck 1 . 1 Division of Biopharmaceutics, Leiden/Amsterdam Center for Drug Research, Leiden University, Leiden, The Netherlands; 2 Centre D Immunologie de Marseille Luminy, INSERM, CNRS, Universite de La Mediterranee, Marseille, France ABCA1 mediates the efflux of cholesterol from macrophage foam cells to lipid-poor apoAI, while SR-BI promotes efflux to mature HDL. The aim of this study was to get further insight into a putative synergistic role of ABCA1 and SR-BI in foam cell formation and atherosclerotic lesion development in vivo. ABCA1-deficient mice were cross-bred with SR-BI-deficient mice and bone marrow transplantation experiments were performed to LDL receptor knockout (LDLr KO) mice using ABCA1xSR-BI double knockouts as donors. To induce atherosclerosis, the mice were challenged with a Western-type diet containing 0.25% cholesterol and 15% fat for 9 weeks. Serum cholesterol levels were only 863±118 mg/dL in ABCA1xSR-BI double knockout transplanted animals, as compared to 1390±98 mg/dL (p<0.01) for single ABCA1 KO, 1600±13 mg/dL (p<0.001) for single SR-BI KO, and 1610±75 mg/dL (p<0.001) for control transplanted animals. Thus, combined deletion of SR-BI and ABCA1 in macrophages resulted in ∼1.8-fold lower serum cholesterol levels. Despite the lower serum cholesterol levels, LDLr KO mice reconstituted with ABCA1xSR-BI double KO bone marrow showed more extreme foam cell formation in macrophages isolated from the peritoneal cavity. Furthermore, atherosclerotic lesion development was more extensive in the LDLr KO mice reconstituted with ABCA1xSR-BI double KO bone marrow (724±51x10E3 μm2 ) as compared to single ABCA1 KO (469±53x10E3 μm2 , P<0.001), SR-BI KO (529±30x10E3 μm2 , P<0.01), and wildtype (307±32x10E3 μm2 , P<0.001) reconstituted animals. In conclusion, combined deletion of macrophage SR-BI and ABCA1 identifies the essential independent function of ABCA1 and SR-BI in cholesterol efflux from macrophages and atherosclerotic lesion development.
WO11 OBESITY AND VISCERAL FAT AS A RISK FACTOR OF CARDIOVASCULAR DISEASES WO11-OR-3
ATHEROSCLEROSIS IN APOLIPOPROTEIN E DEFICIENT MICE IS ACCELERATED BY INFLAMMATORY ADIPOSE TISSUE
Methods: A model of inflammatory fat was produced by transplantation of visceral adipose tissue. To establish feasibility of fat depot transplantation, epididymal fat pads were harvested from WT mice and initially transplanted to ob/ob mice (n=5) deficient in leptin. WT fat transplantation produced physiologic leptin levels, prevented obesity, and restored fertility in ob/ob mice. However, the transplanted fat depots were associated with increased macrophage infiltration compared to endogenous fat (38.86±5.08 vs. 4.97±0.68% of total number of cells, p=0.00013). To determine if this inflammatory adipose depot could affect vascular disease in mice, epididymal fat depots were transplanted to atherosclerotic-prone mice deficient in apolipoprotein E (ApoEKO) (n=6) and compared to a control group of ApoEKO mice that underwent sham operation (n=6). Both groups were fed normal chow for 37 weeks. Results: There was no difference in total cholesterol or in body weight between the groups. However, ApoEKO mice transplanted with visceral fat had increased leptin (0.32±0.07 vs. 1.06±0.28 ng/ml, p=0.022), resistin (1.45±0.17 vs. 1.89±0.14 ng/ml, p=0.039), MCP-1 (278.75±37.25 vs. 494.64±49.81 pg/ml, p=0.003) and adiponectin (47.53±2.74 vs. 63.59±5.05 mg/ml, p=0.012) compared to control group. Furthermore, there was a 40% increase in the atherosclerotic surface area in the fat transplanted group (16.42±1.65 vs. 27.50±4.31%, p=0.025). Conclusion: Increased adipose tissue-related inflammation leads to increased atherosclerosis in mice. WO11-OR-4
ABDOMINAL OBESITY IS RELATED WITH CHANGES IN VASCULAR REACTIVITY OF HUMAN INTERNAL MAMMARY ARTERY INDEPENDENTLY OF OTHER CARDIOVASCULAR RISK FACTORS
C.F. Rueda-Clausen 1 , I.C. Bolivar 1 , J. Calderon 2 , M.S. Fernandez-Alfonso 3 , M. Carreno 2 , V. Cachofeiro 4 , M.P. Oubina 4 , P. Lopez-Jaramillo 1 , V. Lahera 4 . 1 Grupo Via L-Arginina Oxido Nitrico VILANO. Fundacion Cardiovascular de Colombia, Bucaramanga, Colombia; 2 Grupo de Cirugia Cardiovascular QUIRON, Fundacion Cardiovascular de Colombia, Bucaramanga, Colombia; 3 Instituto Pluridisciplinar, Universidad Complutense de Madrid, Madrid, Spain; 4 Laboratorio de Fisiopatologia Cardiovascular, Facultad de Medicina, Universidad Complutense de Madrid, Madrid, Spain A growing body of evidence suggests that abdominal obesity(AO) may play a direct role in initiating atherosclerosis as fat cells are capable of affecting endothelial function through a variety of mechanisms. The aim of this study is to evaluate changes of in-vitro vascular reactivity related with AO (waist circumference ≥80cm for women or ≥90cm for men) in subjects who underwent coronary artery bypass graft. Subjects without AO (Thin n=17) and sex and age-matched subjects with AO (Obese, n=17) were included in the analysis. Complete medical examination and determinations of glucose, lipid profile, C reactive protein, interleukin 6, interleukin 1β, tumor necrosis factor-α, p-selectin, vascular cell adhesion molecule and leptin were performed. Except for weight, body mass index and waist circumference, no significant differences were observed in other anthropometrical, hemodynamic or metabolic variables between obese and thin subjects. Only plasma leptin levels were higher in obese subjects (6.21±3.34 vs.18.1±13.48 ng/mL, p=0.04) correlating with BMI. Segments of the left internal mammary artery (IMA) were obtained to perform in-vitro vascular reactivity protocols. Relaxations to acetylcholine (10E-10 to 10E-5M)) and to sodium nitroprusside (10E-10 to 10E-5M) were significantly reduced in IMA from obese subjects. Contractile responses to angiotensin II (10E-10 to 10E-6M) were significantly higher in IMA from obese subjects. These results suggest that independently of other cardiovascular risk factors, the presence of abdominal obesity is related with both i) endothelial dysfunction and ii) changes in endothelial-independent relaxations, suggesting changes in vascular structure. Acknowledgment to Sociedad Española de Hipertensión (SHE-LELHA).
M.K. Ohman, Y. Shen, C.I. Obimba, D.T. Eitzman. Department of Internal Medicine, Division of Cardiology, University of Michigan, Ann Arbor, MI, USA Background: Accumulation of visceral adipose tissue is associated with fat leukocyte infiltration. Adipose tissue inflammation may play an important role in vascular complications associated with obesity. 76th Congress of the European Atherosclerosis Society, June 10–13, 2007, Helsinki, Finland
WORKSHOPS
FFA (p=0.003)] and LDL [0.50 μmol/L FFA (p=0.002)]. There were also significant differences between the groups in lipoprotein composition (table). Conclusion: VLDL and LDL from T2DM-MetS women were more susceptible to sPLA2-V lipolysis than those from controls, indicating a higher release of inflammatory mediators and more atherogenic lipoproteins in women with T2DM and MetS in vivo. The differences in lipoprotein composition could affect the susceptibility to sPLA2-V lipolysis by changing the micro environment of the lipoprotein phospholipid surface.
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