Abstract 15293: Modulation of CETP by Dalcetrapib Increased CETP Induced Pre-β-HDL and Macrophage ABCA1 Cholesterol Efflux of Human Plasma in vitro
Introduction: Dalcetrapib selectively modulates cholesteryl ester transfer protein (CETP) activity in vitro. Transfer of cholesteryl esters (CE) between HDL and ApoB-containing lipoproteins is inhibited whereas intra-HDL CE transfer and pre-β-HDL generation are not impaired. In contrast, potent CETP inhibitors (torcetrapib) decreased both activities.
Hypothesis: We assessed the hypothesis that the CETP modulator dalcetrapib will differentially affect CETP induced pre-β-HDL formation and HDL-induced ABCA1-dependent cholesterol efflux compared with CETP inhibitors.
Methods: Human plasma was incubated at 37°C for 21 h with and without recombinant human (rh)CETP and CETP modulator or inhibitor. HDL was isolated by precipitating ApoB-containing lipoproteins. HDL samples were added to the mouse macrophage cell line J774, with and without cAMP, to quantify ATP-binding cassette transporter A1 (ABCA1)-dependent efflux. Pre-β1-HDL formation was assessed by agarose gel electrophoresis and ELISA.
Results: Pre-β-HDL, generated by incubation of human plasma, increased dose-dependently with added rhCETP and was associated with a dose-dependent increase in ABCA1-specific efflux. ABCA1 efflux from incubated plasma-HDL samples was 3.8±1.2% (mean ± SD) vs 0.5±0.5% for non-incubated (p<0.05). Addition of 3.7, 7.5, 15.0 and 30.0 μ g/mL rhCETP to plasma (final concentration) increased ABCA1 efflux to 3.9 ±1.3, 5.9±1.4, 7.7±1.7 and 9.4±2.0%, respectively. Addition of dalcetrapib did not impair pre-β-HDL formation and ABCA1-dependent efflux. In the presence of added rhCETP (30.0 μ g/mL), dalcetrapib (10 μ M) increased pre-β-HDL and ABCA1-specific efflux 1.7-fold and 2.5-fold (p<0.05) respectively. In contrast, potent CETP inhibitors (torcetrapib) did not stimulate ABCA1-specific efflux.
Conclusions: These data suggest that CETP plays a key role in generating pre-β-HDL in human plasma and ABCA1-dependent efflux. The two effects of CETP 1) mediating transfer of CE between HDL and LDL/VLDL and 2) remodeling of HDL, could be uncoupled by the selective CETP modulator dalcetrapib, whereas non-selective CETP inhibitors abolish both effects. The ongoing phase III dal-OUTCOMES study will assess the relevance of these findings in the clinical setting.
- © 2011 by American Heart Association, Inc.