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(Circulation. 2005;111:3112-3118.)
© 2005 American Heart Association, Inc.

Vascular Medicine

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; G.M. Anantharamaiah, PhD

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

Correspondence to G.M. Anantharamaiah, PhD, 1808 7th Ave S, DH-668, UAB Medical Center, Birmingham, AL 35294. E-mail ananth{at}uab.edu

Received August 2, 2004; revision received December 3, 2004; accepted February 24, 2005.

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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