STATIN–INDUCED DECREASE IN ABCA1 EXPRESSION VIA MIR33 INDUCTION MAY COUNTERACT CHOLESTEROL EFFLUX BY HIGH–DENSITY LIPOPROTEINS RAISED WITH THE CHOLESTERYL ESTER TRANSFER PROTEIN MODULATOR DALCETRAPIB
Vascular Medicine
Background
Reverse cholesterol transport is believed to be an important function of high–density lipoprotein (HDL). HDL–cholesterol from patients treated with the cholesteryl ester transfer protein (CETP) modulator dalcetrapib has been shown to increase cholesterol efflux in vitro in the absence of statin. However, in a Phase 3 trial in which almost all patients were treated with a statin, dalcetrapib failed to reduce cardiovascular events despite significant increases in HDL–C and apolipoprotein A1 concentrations. As a possible explanation for these disparate findings, we investigated the possibility that statins suppress expression of ABC transporters and thereby reduce cholesterol efflux by HDL.
Methods
Potential mechanisms for a statin/cholesterol efflux interaction were investigated in vitro by measuring: 1) expression of ABCA1 and miR33 in human THP–1 monocytes 2) ABCA1 mRNA and cholesterol efflux in mouse J774 macrophages incubated with isolated HDL from pooled human plasma.
Results
In THP–1 cells loaded with acetylated LDL, incubation with 1μM atorvastatin increased microRNA33 (miRNA) by 33% (P<0.05), and decreased ABCA1 mRNA and ABCG1 mRNA by 47% (P<0.05) and 27% (NS) respectively. In J774 mouse macrophages labeled with 3H–cholesterol, ABCA1 mRNA and cholesterol efflux via ABCA1 were decreased by 1μM of statins, with the following order of potency: simvastatin>pitavastatin>atorv astatin >rosuvastatin >pravastatin; ie, the most hydrophilic statins exerted the smallest effects.
Conclusions
This study suggests the possibility that statin treatment may increase miR33 expression, resulting in decreased ABCA1 expression and cholesterol efflux via this transporter. These findings might explain the failure of dalcetrapib to reduce cardiovascular events among patients treated with statins, despite an increase in HDL–C and apolipoprotein A1 concentration.
Footnotes
Moderated Poster Contributions
Poster Sessions, Expo North
Saturday, March 09, 2013, 10:00 a.m.–10:45 a.m.
Session Title: Vascular Medicine Basic: Atherogenesis
Abstract Category: 33. Vascular Medicine: Basic
Presentation Number: 1125M–167
