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Reconstituted HDL elicits marked changes in plasma lipids following single-dose injection in C57Bl/6 mice.
- Source :
-
Journal of cardiovascular pharmacology and therapeutics [J Cardiovasc Pharmacol Ther] 2012 Sep; Vol. 17 (3), pp. 315-23. Date of Electronic Publication: 2011 Nov 08. - Publication Year :
- 2012
-
Abstract
- High-density lipoprotein (HDL)-targeting therapies, including reconstituted HDL (rHDL), are attractive agents for treating dyslipidemia and atherosclerosis, as they may increase HDL levels and enhance therapeutic activities associated with HDL, including reverse cholesterol transport (RCT). Using CSL-111, a rHDL consisting of native human apolipoprotein AI (hApoAI) and phospholipids, we characterized the acute effects of rHDL administration in C57Bl/6 mice to (i) further our understanding of the mechanism of action of rHDL, and (ii) evaluate the usefulness of the mouse as a preclinical model for HDL-targeting therapies. After a single injection of CSL-111, there was a dose- and time-dependent increase of hApoAI, human pre-β HDL, total cholesterol, and triglycerides in serum, consistent with the effects of CSL-111 in humans. However, unlike in humans, there was no measurable increase in cholesteryl esters. Evaluated ex vivo, the ATP binding cassette A1 (ABCA1)- and scavenger receptor type BI (SR-BI)-dependent cholesterol efflux capacity of serum from CSL-111-treated mice was increased compared with serum from vehicle-treated animals. Fractionation by size exclusion chromatography of lipoproteins in serum from treated mice revealed hApoAI in particles the size of endogenous HDL and slightly larger, cholesterol-enriched particles of all sizes, including sizes distinct from endogenous HDL or CSL-111 itself, and triglyceride-enriched particles the size of very-low-density lipoprotein (VLDL). These results suggest that in mouse blood CSL-111 is remodeled and generates enhanced cholesterol efflux capacity which increases mobilization of free cholesterol from peripheral tissues. Our findings complement the previous reports on CSL-111 in human participants and provide data with which to evaluate the potential utility of mouse models in mechanistic studies of HDL-targeting therapies.
- Subjects :
- Animals
COUP Transcription Factor II genetics
COUP Transcription Factor II metabolism
Cell Line
Cholesterol metabolism
Cholesterol, HDL administration & dosage
Dose-Response Relationship, Drug
Gene Expression Regulation
High-Density Lipoproteins, Pre-beta metabolism
Injections, Intravenous
Macrophages drug effects
Macrophages metabolism
Male
Mice
Mice, Inbred C57BL
Phosphatidylcholines
Cholesterol, HDL pharmacology
Lipids blood
Subjects
Details
- Language :
- English
- ISSN :
- 1940-4034
- Volume :
- 17
- Issue :
- 3
- Database :
- MEDLINE
- Journal :
- Journal of cardiovascular pharmacology and therapeutics
- Publication Type :
- Academic Journal
- Accession number :
- 22067613
- Full Text :
- https://doi.org/10.1177/1074248411426144