A new HDL mimetic peptide that stimulates cellular cholesterol efflux with high efficiency greatly reduces atherosclerosis in mice.
Here, we report the creation of a single-helix peptide (ATI-5261) that stimulates cellular cholesterol efflux with K(m) molar efficiency approximating native apolipoproteins. Anti-atherosclerosis activity of ATI-5261 was evaluated in LDLR(-/-) and apolipoprotein (apo)E(-/-) mice approximately 5-7 months of age, following 13-18 weeks on a high-fat Western diet (HFWD). Treatment of fat-fed LDLR(-/-) mice with daily intraperitoneal injections of ATI-5261 (30 mg/kg) for 6 weeks reduced atherosclerosis by 30%, as judged by lesion area covering the aorta (7.9 +/- 2 vs.11.3 +/- 2.5% control, P = 0.011) and lipid-content of aortic sinus plaque (25 +/- 5.8 vs. 33 +/- 4.9% control, P = 0.014). In apoE(-/-) mice, the peptide administered 30 mg/kg ip on alternate days for 6 weeks reduced atherosclerosis by approximately 45% (lesion area = 15 +/- 7 vs. 25 +/- 8% control, P = 0.00016; plaque lipid-content = 20 +/- 6 vs. 32 +/- 8% control, P < 0.0001). Similar reductions in atherosclerosis were achieved using ATI-5261:POPC complexes. Single intraperitoneal injection of ATI-5261 increased reverse cholesterol transport from macrophage foam-cells to feces over 24-48 h. In summary, relatively short-term treatment of mice with the potent cholesterol efflux peptide ATI-5261 reduced substantial atherosclerosis. This was achieved using an L-amino acid peptide, in the presence of severe hypercholesterolemia/HFWD, and did not require daily injections or formulation with phospholipids when administered via intraperitoneal injection.
Bielicki
John K
JK
Lawrence Berkeley National Laboratory, Donner Laboratory, MS1-267, University of California, Berkeley, CA 94720, USA. jkbielicki@lbl.gov
Zhang
Haiyan
H
Cortez
Yuan
Y
Zheng
Ying
Y
Narayanaswami
Vasanthy
V
Patel
Arti
A
Johansson
Jan
J
Azhar
Salman
S
D000595:Amino Acid Sequence; D000818:Animals; D001057:Apolipoproteins E / Q000737:chemistry; D050197:Atherosclerosis / Q000150:complications / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology*; D001692:Biological Transport / Q000187:drug effects; D040761:Biomimetic Materials / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D002784:Cholesterol / Q000378:metabolism*; D015195:Drug Design; D006949:Hyperlipidemias / Q000150:complications; D036341:Intercellular Signaling Peptides and Proteins; D008075:Lipoproteins, HDL / Q000378:metabolism*; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008969:Molecular Sequence Data; D010455:Peptides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D012995:Solubility
C585585:ATI-5261; D001057:Apolipoproteins E; D036341:Intercellular Signaling Peptides and Proteins; D008075:Lipoproteins, HDL; D010455:Peptides; D002784:Cholesterol