Apolipoprotein E mimetic Peptide dramatically lowers plasma cholesterol and restores endothelial function in watanabe heritable hyperlipidemic rabbits.
BACKGROUND
These studies were designed to determine whether the dual-domain peptide with a class A amphipathic helix linked to the receptor-binding domain of apolipoprotein (apo) E (Ac-hE-18A-NH2) possesses both antidyslipidemic and antiinflammatory properties.


RESULTS
A single bolus (15 mg/kg IV) of Ac-hE-18A-NH2 that contains LRKLRKRLLR (141- to 150-residue region of apo E) covalently linked to apo A-I mimetic peptide 18A not only reduced plasma cholesterol levels (baseline, 562+/-29.0 mg/dL versus 287.7+/-22.0 mg/dL at 18 hours, P<0.001) in the Watanabe heritable hyperlipidemic rabbit model but also significantly improved arterial endothelial function. This improvement was associated with a reduction in 2 markers of oxidative stress. First, the plasma lipid hydroperoxide content was reduced significantly, an effect associated with a 5-fold increase in HDL paraoxonase activity. Second, the formation of superoxide anion, a scavenger of nitric oxide, was also significantly reduced in arteries of these animals.


CONCLUSIONS
Because dyslipidemia and endothelial dysfunction are common features of the atherosclerotic disease process, this unique dual-domain peptide has ideal composite properties that ameliorate key contributory factors to atherosclerosis.
Gupta
Himanshu
H
Department of Medicine, University of Alabama at Birmingham, AL, USA.
White
C Roger
CR
Handattu
Shaila
S
Garber
David W
DW
Datta
Geeta
G
Chaddha
Manjula
M
Dai
Lijun
L
Gianturco
Sandra H
SH
Bradley
William A
WA
Anantharamaiah
G M
GM
D000818:Animals; D001057:Apolipoproteins E / Q000737:chemistry* / Q000627:therapeutic use; D050197:Atherosclerosis / Q000188:drug therapy / Q000517:prevention & control; D002784:Cholesterol / Q000097:blood*; D004730:Endothelium, Vascular / Q000187:drug effects / Q000473:pathology / Q000502:physiology; D006949:Hyperlipidemias / Q000188:drug therapy* / Q000473:pathology; D007249:Inflammation / Q000188:drug therapy; D008052:Lipid Metabolism, Inborn Errors / Q000188:drug therapy; D008055:Lipids / Q000097:blood; D008297:Male; D018716:Molecular Mimicry; D018384:Oxidative Stress / Q000187:drug effects; D010446:Peptide Fragments / Q000138:chemical synthesis / Q000494:pharmacology / Q000627:therapeutic use; D010455:Peptides / Q000138:chemical synthesis / Q000494:pharmacology* / Q000627:therapeutic use; D011817:Rabbits; D013481:Superoxides / Q000032:analysis
D001057:Apolipoproteins E; D008055:Lipids; D010446:Peptide Fragments; D010455:Peptides; D013481:Superoxides; D002784:Cholesterol