Reverse D4F, an apolipoprotein-AI mimetic peptide, inhibits atherosclerosis in ApoE-null mice.
OBJECTIVE
Synthetic class A amphipathic helical peptide analogs of apolipoprotein-AI (apoAI; with varied phenylalanine residues) are emerging therapeutic approaches under investigation for atherosclerosis. Utilizing retroinverso sequencing, we designed reverse-D4F (Rev-D4F) peptide with 18 d-amino acids containing 4 phenylalanine residues and reverse order that allows the side chain residues to be of exact alignment and superimposable to those of the parent l-amino acid peptide. This study examined the effect of Rev-D4F on atherosclerosis in apolipoprotein E (apoE)-null mice and the underlying mechanisms.


METHODS
ApoE-null mice were fed a chow diet and administered water (control), Rev-D4F, or L4F mimetic peptides (0.4 mg/mL, equivalent to 1.6 mg/d) orally in drinking water for 6 weeks. Aortic root atherosclerotic lesion area, lesion macrophage content, and the ability of plasma high-density lipoprotein (HDL) to influence monocyte chemotaxis were measured.


RESULTS
Rev-D4F significantly decreased aortic sinus atherosclerotic lesion area and lesion macrophage content without affecting plasma total and HDL-cholesterol levels in apoE-null mice. The HDL from Rev-D4F-treated mice showed enhanced anti-inflammatory monocyte chemotactic activity, while low-density lipoprotein (LDL) exhibited reduced proinflammatory activity. In in vitro studies, Rev-D4F inhibited LDL oxidation, endothelial cell vascular cell adhesion molecule 1 (VCAM-1), and monocyte chemotactic factor 1 (MCP-1) expression, and monocyte adhesion to aortic endothelial cells.


CONCLUSIONS
The Rev-D4F inhibits atherosclerosis by inhibiting endothelial inflammatory/oxidative events and improving HDL function. The data suggest that Rev-D4F may be an effective apoAI mimetic peptide for further development in preventing atherosclerosis.
Department of Veterans Affairs Healthcare System, Atherosclerosis Research Center, Long Beach, CA 90822, USA.
Shucun
S
Qin
Vaijinath S
VS
Kamanna
Jack H
JH
Lai
Tianjiao
T
Liu
Shobha H
SH
Ganji
Linhua
L
Zhang
William W
WW
Bachovchin
Moti L
ML
Kashyap
D000818:Animals; D001011:Aorta / Q000166:cytology; D016632:Apolipoprotein A-I / Q000494:pharmacology*; D001057:Apolipoproteins E / Q000235:genetics / Q000378:metabolism*; D050197:Atherosclerosis / Q000517:prevention & control*; D001835:Body Weight / Q000187:drug effects; D018932:Chemokine CCL2 / Q000235:genetics / Q000378:metabolism; D018920:Coculture Techniques; D042783:Endothelial Cells; D005260:Female; D006801:Humans; D008055:Lipids / Q000097:blood; D008264:Macrophages / Q000187:drug effects; D051379:Mice; D018345:Mice, Knockout; D010455:Peptides / Q000494:pharmacology*
D016632:Apolipoprotein A-I; D001057:Apolipoproteins E; C491768:Ccl2 protein, mouse; D018932:Chemokine CCL2; C465468:D-4F peptide; C472885:L-4F peptide; D008055:Lipids; D010455:Peptides; C000607988:reverse-D-4F peptide