High-Density Lipoprotein Subfractions and Cholesterol Efflux Capacities After Infusion of MDCO-216 (Apolipoprotein A-IMilano/Palmitoyl-Oleoyl-Phosphatidylcholine) in Healthy Volunteers and Stable Coronary Artery Disease Patients.

Abstract

OBJECTIVE:

To determine effects of single ascending doses of MDCO-216 on high-density lipoprotein (HDL) subfractions in relation to changes in cholesterol efflux capacity in healthy volunteers and in patients with stable angina pectoris.

APPROACH AND RESULTS:

Doses of 5- (in volunteers only), 10-, 20-, 30-, and 40-mg/kg MDCO-216 were infused during 2 hours, and plasma and serum were collected during 30 days. Plasma levels of HDL subfractions were assessed by 2-dimensional gel electrophoresis, immunoblotting, and image analysis. Lipoprotein particle concentrations and sizes were also assessed by proton nuclear magnetic resonance ((1)H-NMR). There was a rapid dose-dependent increase of total apolipoprotein A-I (apoA-I) in pre-β1, α-1, and α-2 HDL levels and decrease in α-3 and α-4 HDL. Using a selective antibody apoA-IMilano was detected in the large α-1 and α-2 HDL on all doses and at each time point. ApoA-IMilano was also detected at the α-4 position but only at high doses. (1)H-NMR analysis similarly showed a rapid and dose-dependent shift from small- to large-sized HDL particles. The increase of basal and ATP-binding cassette transporter A1-mediated efflux capacities reported previously correlated strongly and independently with the increase in pre-β1-HDL and α-1 HDL, but not with that in α-2 HDL.

CONCLUSIONS:

On infusion, MDCO-216 rapidly eliminates small HDL and leads to formation of α-1 and α-2 HDL containing both wild-type apoA-I and apoA-IMilano. In this process, endogenous apoA-I is liberated appearing as pre-β1-HDL. In addition to pre-β1-HDL, the newly formed α-1 HDL particle containing apoA-I Milano may have a direct effect on cholesterol efflux capacity.

• Authors: Herman J Kempen, Bela F Asztalos, Matthijs Moerland, Elias Jeyarajah, James Otvos, David G Kallend, S Eralp Bellibas, Peter L J Wijngaard
• Journal: Arteriosclerosis, thrombosis, and vascular biology (Arterioscler Thromb Vasc Biol) Vol. 36 Issue 4 Pg. 736-42 (Apr 2016) ISSN: 1524-4636 [Electronic] United States
• PMID: 26916733 (Publication Type: Journal Article, Randomized Controlled Trial)
• Copyright: © 2016 American Heart Association, Inc.

Chemical References

• ABCA1 protein, human
• ATP Binding Cassette Transporter 1
• Anticholesteremic Agents
• Apolipoprotein A-I
• Biomarkers
• Drug Combinations
• High-Density Lipoproteins, Pre-beta
• Lipoproteins, HDL
• MDCO-216
• Phosphatidylcholines
• Cholesterol

Topics

• ATP Binding Cassette Transporter 1 (metabolism)
• Anticholesteremic Agents (administration & dosage, blood)
• Apolipoprotein A-I (administration & dosage, blood)
• Biomarkers (blood)
• Blotting, Western
• Case-Control Studies
• Cholesterol (blood)
• Coronary Artery Disease (blood, diagnosis, drug therapy)
• Dose-Response Relationship, Drug
• Drug Combinations
• Electrophoresis, Gel, Two-Dimensional
• Healthy Volunteers
• High-Density Lipoproteins, Pre-beta (blood)
• Humans
• Infusions, Intravenous
• Lipoproteins, HDL (blood)
• Macrophages (drug effects, metabolism)
• Netherlands
• Particle Size
• Phosphatidylcholines (administration & dosage, blood)
• Proton Magnetic Resonance Spectroscopy
• Time Factors
• Treatment Outcome