Published Online
on June 6, 2005

A more recent version of this article appeared on June 14, 2005

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Submitted on August 2, 2004
Revised on December 3, 2004
Accepted on February 24, 2005

Apolipoprotein E Mimetic Peptide Dramatically Lowers Plasma Cholesterol and Restores Endothelial Function in Watanabe Heritable Hyperlipidemic Rabbits

Himanshu Gupta MD, C. Roger White PhD, Shaila Handattu PhD, David W. Garber PhD, Geeta Datta PhD, Manjula Chaddha PhD, Lijun Dai PhD, Sandra H. Gianturco PhD, William A. Bradley PhD, and G. M. Anantharamaiah PhD^*

From the Departments of Medicine, Biochemistry, and Molecular Genetics and the Atherosclerosis Research Unit, University of Alabama at Birmingham.

^* To whom correspondence should be addressed. E-mail: ananth{at}uab.edu.

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.

Methods and 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.

Key words: lipoproteins • endothelium • metabolism • nitric oxide • arteriosclerosis

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