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Increased lipoprotein binding to arterial proteoglycans and normal macrophage cholesterol efflux capacity define the pro-atherogenic feature of CKD dyslipidemia
Abstracts / Atherosclerosis XXX (2016) e236ee264 ĂConclusions: Our findings show that osteogenic conditions promote
increased DRP1 expression and that DRP1 inhibition prevents human SMC calcification. These results support a role of DRP1 in human vascular calcification, a novel area of exploration for the development of new therapies.
EAS16-0812, WORKSHOP 2.1: LIPOPROTEINS AND EXTRACELLULAR MATRIX. INCREASED LIPOPROTEIN BINDING TO ARTERIAL PROTEOGLYCANS AND NORMAL MACROPHAGE CHOLESTEROL EFFLUX CAPACITY DEFINE THE PRO-ATHEROGENIC FEATURE OF CKD DYSLIPIDEMIA M. Pedrelli 1, P. Stenvinkel 2, M.E. Minniti 3, K. Emma 3, A. Dikkers 4, S. Ebtehaj 4, M. Gomaraschi 5, P. Barany 2, A.R. Qureshi 2, G. Camejo 3, B. €o €rni 6, U. Tietge 4, L. Calabresi 5, E. Hurt-Camejo 7, P. Lindholm 2, K. O Parini 8. 1 Karolinska Institutet and AstraZeneca, Division Clinical Chemistry, Department of Laboratory Medicine, Karolinska Intitutet and Translational Science, CVMD iMed, AstraZeneca R&D, Stockholm, Sweden; 2 Karolinska Institutet, Division of Renal Medicine and Baxter Novum, Department of Clinical Science, Intervention and Technology, Stockholm, Sweden; 3 Karolinska Institutet, Division of Clinical Chemistry, Department of Laboratory Medicine, Stockholm, Sweden; 4 University of Groningen, University Medical Center Groningen, Department of Pediatrics, Groningen, di Milano, Centro Enrica Grossi Paoletti, Netherlands; 5 Universita Dipartimento di Scienze Farmacologiche e Biomolecolari, Milano, Italy; 6 Wihuri Research Institute, Atherosclerosis Research Laboratory, Helsinki, Finland; 7 AstraZeneca and Karolinska Institutet, Translational Science, CVMD iMed, AstraZeneca R&D, Division Clinical Chemistry, Department of Laboratory Medicine, Karolinska Intitutet, Gothenburg, Sweden; 8 Karolinska Institutet, Division of Clinical Chemistry, Department of Laboratory Medicine and Department of Medicine, Stockholm, Sweden Objectives: In chronic kidney disease (CKD), the decline of estimated glomerular filtration rate (eGFR) associates with increased cardiovascular mortality, which is not fully explained by the dyslipidemia developed by these subjects. Our aim was to study the association of eGFR decline with changes in lipoprotein composition, size and selected functionalities: for HDL, the in vitro cholesterol efflux capacity (CEC) and its antioxidant effects, a potential athero-protective mechanism, and, for LDL, the binding to arterial proteoglycans, an atherogenic mechanism. Methods: CKD patients, non-diabetic and naïve to dialysis and lipid lowering treatment, were divided into two groups: eGFR>60 mL/min/1.73 m2 (n¼19) or eGFR30 mL/min/1.73 m2 (n¼39). Results: LDL and HDL of patients with lower eGFR were smaller than those in patients with eGFR>60. In subjects with eGFR30, whole and apoB-depleted serum were less efficient cholesterol acceptors via aqueous diffusion and SR-BI, but more efficient in promoting efflux by ABCA1. This was due to presence of higher proportion of plasma small HDL and preb-HDL. Consequently, no differences in total macrophage CEC were observed. HDL capacity to prevent LDL-oxidation did not differ between groups. Binding of plasma to human arterial proteoglycans was higher in patients with eGFR30 than in those with eGFR>60, due to smaller size of LDL. Conclusions: Low eGFR associates with decreased size of LDL and depletion of large HDL particles, which in turn increase binding of apoB-containing lipoproteins to arterial proteoglycans. This suggests a potential mechanism that could contribute to the increased cardiovascular mortality in CKD patients.
EAS16-0268, WORKSHOP 2.1: LIPOPROTEINS AND EXTRACELLULAR MATRIX. BROWN AND BEIGE ADIPOCYTE ACTIVITY CONTROLS METABOLIC FLUX THROUGH THE HDL COMPARTMENT N. Schaltenberg 1, A. Bartelt 2, J. Clara 1, A. Worthmann 1, C.M. Lisa 1, R. € rg 1. 1 University Franz 3, H. Markus 1, K.N. Stefan 1, S. Ludger 1, H. Jo
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Medical Center Hamburg-Eppendorf, Department of Biochemistry and Cell Biology, Hamburg, Germany; 2 Harvard School of Public Health, Department of Genetics and Complex Diseases and Sabri Ülker Center, Boston, USA; 3 University Medical Center Hamburg-Eppendorf, Department of Internal Medicine, Hamburg, Germany Objectives: Brown adipose tissue (BAT) is the primary organ for heat production in small mammals in response to cold and it is also present and active in humans. While cold is the natural stimulus, BAT activation can also be achieved by treatment with selective b3-adrenergic receptor agonists such as CL316,243 (CL). Previously we demonstrated that BAT activation reduces triglyceride levels via a lipoprotein lipase (LPL) dependent process, decreases remnant cholesterol levels and protects from atherosclerosis. However, the relevance of BAT for the metabolism of high-density lipoprotein (HDL) remains unknown and therefore we investigated the impact of BAT activation on HDL concentration, composition and function. Methods: For BAT activation, C57BL/6 wild-type, ApoE3L.CETP, adipocytespecific LPL knock-out, and scavenger receptor-BI knock-out mice were either exposed to cold or injected with the b3-adrenergic agonist CL316.243. Lipoproteins were isolated and their composition was determined by high-resolution, full scan mass spectrometry. Metabolic turnover studies were performed to analyze clearance and cholesterol uptake of radiolabeled HDL into different tissues. By injection of cholesterol-labeled macrophages we determined in vivo reverse cholesterol transport in BATactivated mice. Results: HDL isolated from BAT-activated mice displayed a characteristic lipidomic fingerprint, which was associated with increased macrophageto-feces cholesterol transport mediated by scavenger receptor-BI. Mechanistically, we show that lipolysis by adipocyte LPL is the driving force of HDL remodeling and increased HDL turnover. Conclusions: Our findings corroborate the notion that systemic metabolic flux regulated by the high metabolic activity of thermogenic adipocytes determines the atheroprotective properties of HDL.
EAS16-1052, WORKSHOP 3.1: NOVEL THERAPIES. COMPARATIVE EFFECTS OF CHOLESTERYL ESTER TRANSFER PROTEIN INHIBITION, STATIN AND EZETIMIBE THERAPY ON ATHEROGENIC AND PROTECTIVE LIPID FACTORS: THE ACCENTUATE TRIAL S. Nicholls 1, K. Ray 2, C. Ballantyne 3, L. Beacham 4, D. Miller 4, G. Ruotolo 4, J. Riesmeyer 4. 1 South Australian Health and Medical Research Institute, Heart Health, Adelaide, Australia; 2 Imperial College London, Cardiology, London, United Kingdom; 3 Baylor College of Medicine, Cardiovascular Medicine, Houston, USA; 4 Eli Lilly and Company, Cardiovascular Medicine, Indianapolis, USA Objectives: To compare effects of adding cholesteryl ester transfer protein inhibitor, evacetrapib, ezetimibe or increasing statin dose in atorvastatin treated patients at high vascular risk on atherogenic and protective lipid parameters. Methods: 366 patients with atherosclerotic cardiovascular disease(ASCVD) and/or diabetes were treated with atorvastatin 40 mg/day for 28 days prior to randomization to atorvastatin 40 mg plus evacetrapib 130 mg, atorvastatin 80 mg, atorvastatin 40 mg plus ezetimibe 10 mg or atorvastatin 40 mg daily for 90 days at 64 centers in the United States. Effects on atherogenic and protective lipid parameters were investigated. Results: Addition of evacetrapib produced greater reductions in LDL-C (-33%), compared with ezetimibe (-27%, p¼0.045) and increasing atorvastatin dose (-6%, p<0.001). In parallel, evacetrapib produced a greater increase in HDL-C (+125%) compared with ezetimibe (-2%, p<0.001) and increasing statin dose (-6%, p<0.001). Evacetrapib increased apoA-I (46%), apoC-III (50%), apoE (28%) and Lp(a) (29%) superior to ezetimibe and increasing statin dose (p<0.001). Evacetrapib decreased apoB by 23% compared to 19% with ezetimibe (p¼0.062) and 7% with increased statin dose (p<0.001). Increases in ABCA1 (+14%) and non-ABCA1 (+53%) mediated efflux were observed with evacetrapib. Increases were statistically greater than ezetimibe (p<0.001) and increasing statin dose (p¼0.002) for
increased DRP1 expression and that DRP1 inhibition prevents human SMC calcification. These results support a role of DRP1 in human vascular calcification, a novel area of exploration for the development of new therapies.
EAS16-0812, WORKSHOP 2.1: LIPOPROTEINS AND EXTRACELLULAR MATRIX. INCREASED LIPOPROTEIN BINDING TO ARTERIAL PROTEOGLYCANS AND NORMAL MACROPHAGE CHOLESTEROL EFFLUX CAPACITY DEFINE THE PRO-ATHEROGENIC FEATURE OF CKD DYSLIPIDEMIA M. Pedrelli 1, P. Stenvinkel 2, M.E. Minniti 3, K. Emma 3, A. Dikkers 4, S. Ebtehaj 4, M. Gomaraschi 5, P. Barany 2, A.R. Qureshi 2, G. Camejo 3, B. €o €rni 6, U. Tietge 4, L. Calabresi 5, E. Hurt-Camejo 7, P. Lindholm 2, K. O Parini 8. 1 Karolinska Institutet and AstraZeneca, Division Clinical Chemistry, Department of Laboratory Medicine, Karolinska Intitutet and Translational Science, CVMD iMed, AstraZeneca R&D, Stockholm, Sweden; 2 Karolinska Institutet, Division of Renal Medicine and Baxter Novum, Department of Clinical Science, Intervention and Technology, Stockholm, Sweden; 3 Karolinska Institutet, Division of Clinical Chemistry, Department of Laboratory Medicine, Stockholm, Sweden; 4 University of Groningen, University Medical Center Groningen, Department of Pediatrics, Groningen, di Milano, Centro Enrica Grossi Paoletti, Netherlands; 5 Universita Dipartimento di Scienze Farmacologiche e Biomolecolari, Milano, Italy; 6 Wihuri Research Institute, Atherosclerosis Research Laboratory, Helsinki, Finland; 7 AstraZeneca and Karolinska Institutet, Translational Science, CVMD iMed, AstraZeneca R&D, Division Clinical Chemistry, Department of Laboratory Medicine, Karolinska Intitutet, Gothenburg, Sweden; 8 Karolinska Institutet, Division of Clinical Chemistry, Department of Laboratory Medicine and Department of Medicine, Stockholm, Sweden Objectives: In chronic kidney disease (CKD), the decline of estimated glomerular filtration rate (eGFR) associates with increased cardiovascular mortality, which is not fully explained by the dyslipidemia developed by these subjects. Our aim was to study the association of eGFR decline with changes in lipoprotein composition, size and selected functionalities: for HDL, the in vitro cholesterol efflux capacity (CEC) and its antioxidant effects, a potential athero-protective mechanism, and, for LDL, the binding to arterial proteoglycans, an atherogenic mechanism. Methods: CKD patients, non-diabetic and naïve to dialysis and lipid lowering treatment, were divided into two groups: eGFR>60 mL/min/1.73 m2 (n¼19) or eGFR30 mL/min/1.73 m2 (n¼39). Results: LDL and HDL of patients with lower eGFR were smaller than those in patients with eGFR>60. In subjects with eGFR30, whole and apoB-depleted serum were less efficient cholesterol acceptors via aqueous diffusion and SR-BI, but more efficient in promoting efflux by ABCA1. This was due to presence of higher proportion of plasma small HDL and preb-HDL. Consequently, no differences in total macrophage CEC were observed. HDL capacity to prevent LDL-oxidation did not differ between groups. Binding of plasma to human arterial proteoglycans was higher in patients with eGFR30 than in those with eGFR>60, due to smaller size of LDL. Conclusions: Low eGFR associates with decreased size of LDL and depletion of large HDL particles, which in turn increase binding of apoB-containing lipoproteins to arterial proteoglycans. This suggests a potential mechanism that could contribute to the increased cardiovascular mortality in CKD patients.
EAS16-0268, WORKSHOP 2.1: LIPOPROTEINS AND EXTRACELLULAR MATRIX. BROWN AND BEIGE ADIPOCYTE ACTIVITY CONTROLS METABOLIC FLUX THROUGH THE HDL COMPARTMENT N. Schaltenberg 1, A. Bartelt 2, J. Clara 1, A. Worthmann 1, C.M. Lisa 1, R. € rg 1. 1 University Franz 3, H. Markus 1, K.N. Stefan 1, S. Ludger 1, H. Jo
e237
Medical Center Hamburg-Eppendorf, Department of Biochemistry and Cell Biology, Hamburg, Germany; 2 Harvard School of Public Health, Department of Genetics and Complex Diseases and Sabri Ülker Center, Boston, USA; 3 University Medical Center Hamburg-Eppendorf, Department of Internal Medicine, Hamburg, Germany Objectives: Brown adipose tissue (BAT) is the primary organ for heat production in small mammals in response to cold and it is also present and active in humans. While cold is the natural stimulus, BAT activation can also be achieved by treatment with selective b3-adrenergic receptor agonists such as CL316,243 (CL). Previously we demonstrated that BAT activation reduces triglyceride levels via a lipoprotein lipase (LPL) dependent process, decreases remnant cholesterol levels and protects from atherosclerosis. However, the relevance of BAT for the metabolism of high-density lipoprotein (HDL) remains unknown and therefore we investigated the impact of BAT activation on HDL concentration, composition and function. Methods: For BAT activation, C57BL/6 wild-type, ApoE3L.CETP, adipocytespecific LPL knock-out, and scavenger receptor-BI knock-out mice were either exposed to cold or injected with the b3-adrenergic agonist CL316.243. Lipoproteins were isolated and their composition was determined by high-resolution, full scan mass spectrometry. Metabolic turnover studies were performed to analyze clearance and cholesterol uptake of radiolabeled HDL into different tissues. By injection of cholesterol-labeled macrophages we determined in vivo reverse cholesterol transport in BATactivated mice. Results: HDL isolated from BAT-activated mice displayed a characteristic lipidomic fingerprint, which was associated with increased macrophageto-feces cholesterol transport mediated by scavenger receptor-BI. Mechanistically, we show that lipolysis by adipocyte LPL is the driving force of HDL remodeling and increased HDL turnover. Conclusions: Our findings corroborate the notion that systemic metabolic flux regulated by the high metabolic activity of thermogenic adipocytes determines the atheroprotective properties of HDL.
EAS16-1052, WORKSHOP 3.1: NOVEL THERAPIES. COMPARATIVE EFFECTS OF CHOLESTERYL ESTER TRANSFER PROTEIN INHIBITION, STATIN AND EZETIMIBE THERAPY ON ATHEROGENIC AND PROTECTIVE LIPID FACTORS: THE ACCENTUATE TRIAL S. Nicholls 1, K. Ray 2, C. Ballantyne 3, L. Beacham 4, D. Miller 4, G. Ruotolo 4, J. Riesmeyer 4. 1 South Australian Health and Medical Research Institute, Heart Health, Adelaide, Australia; 2 Imperial College London, Cardiology, London, United Kingdom; 3 Baylor College of Medicine, Cardiovascular Medicine, Houston, USA; 4 Eli Lilly and Company, Cardiovascular Medicine, Indianapolis, USA Objectives: To compare effects of adding cholesteryl ester transfer protein inhibitor, evacetrapib, ezetimibe or increasing statin dose in atorvastatin treated patients at high vascular risk on atherogenic and protective lipid parameters. Methods: 366 patients with atherosclerotic cardiovascular disease(ASCVD) and/or diabetes were treated with atorvastatin 40 mg/day for 28 days prior to randomization to atorvastatin 40 mg plus evacetrapib 130 mg, atorvastatin 80 mg, atorvastatin 40 mg plus ezetimibe 10 mg or atorvastatin 40 mg daily for 90 days at 64 centers in the United States. Effects on atherogenic and protective lipid parameters were investigated. Results: Addition of evacetrapib produced greater reductions in LDL-C (-33%), compared with ezetimibe (-27%, p¼0.045) and increasing atorvastatin dose (-6%, p<0.001). In parallel, evacetrapib produced a greater increase in HDL-C (+125%) compared with ezetimibe (-2%, p<0.001) and increasing statin dose (-6%, p<0.001). Evacetrapib increased apoA-I (46%), apoC-III (50%), apoE (28%) and Lp(a) (29%) superior to ezetimibe and increasing statin dose (p<0.001). Evacetrapib decreased apoB by 23% compared to 19% with ezetimibe (p¼0.062) and 7% with increased statin dose (p<0.001). Increases in ABCA1 (+14%) and non-ABCA1 (+53%) mediated efflux were observed with evacetrapib. Increases were statistically greater than ezetimibe (p<0.001) and increasing statin dose (p¼0.002) for