Abstract
Intravenous administration of apolipoprotein (apo) A-I complexed with phospholipid has been shown to rapidly reduce plaque size in both animal models and humans. Short synthetic amphipathic peptides can mimic the antiatherogenic properties of apoA-I and have been proposed as alternative therapeutic agents. In this study, we investigated the atheroprotective effect of the 5A peptide, a bihelical amphipathic peptide that specifically effluxes cholesterol from cells by ATP-binding cassette transporter 1 (ABCA1). 5A stimulated a 3.5-fold increase in ABCA1-mediated efflux from cells and an additional 2.5-fold increase after complexing it with phospholipid (1:7 mol/mol). 5A-palmitoyl oleoyl phosphatidyl choline (POPC), but not free 5A, was also found to promote cholesterol efflux by ABCG1. When incubated with human serum, 5A-POPC bound primarily to high-density lipoprotein (HDL) but also to low-density lipoprotein (LDL) and promoted the transfer of cholesterol from LDL to HDL. Twenty-four hours after intravenous injection of 5A-POPC (30 mg/kg) into apoE-knockout (KO) mice, both the cholesterol (181%) and phospholipid (219%) content of HDL significantly increased. By an in vivo cholesterol isotope dilution study and monitoring of the flux of cholesterol from radiolabeled macrophages to stool, 5A-POPC treatment was observed to increase reverse cholesterol transport. In three separate studies, 5A when complexed with various phospholipids reduced aortic plaque surface area by 29 to 53% (n = 8 per group; p < 0.02) in apoE-KO mice. No signs of toxicity from the treatment were observed during these studies. In summary, 5A promotes cholesterol efflux both in vitro and in vivo and reduces atherosclerosis in apoE-KO mice, indicating that it may be a useful alternative to apoA-I for HDL therapy.
Footnotes
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This work was supported by the Intramural Research Program of the National Institutes of Health, National Heart, Lung, and Blood Institute. W.D. was supported by the National Health and Medical Research Council of Australia [Australian Postgraduate Award 526709]. D.S. is a Fellow of the Health and Medical Research Council of Australia [Award 586607].
Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
doi:10.1124/jpet.110.167890.
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ABBREVIATIONS:
- apo
- apolipoprotein
- Athero
- atherosclerosis
- HDL
- high-density lipoprotein
- LDL
- low-density lipoprotein
- RCT
- reverse cholesterol transport
- POPC
- palmitoyl oleoyl phosphatidyl choline
- ABC
- ATP-binding cassette transporter
- KO
- knockout
- DPPC
- dipalmitoyl phosphatidylcholine
- SM
- sphingomyelin
- FPLC
- fast-protein liquid chromatography
- BHK
- baby hamster kidney
- BA
- bile acids
- NS
- neutral sterols
- 13C2-C
- [2,3-13C2]cholesterol
- GC
- gas chromatography
- MS
- mass spectrometry
- Received March 10, 2010.
- Accepted May 13, 2010.
- U.S. Government work not protected by U.S. copyright
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