Apolipoprotein e mimetic peptide dramatically lowers plasma cholesterol and restores endothelial function in watanabe heritable hyperlipidemic rabbits

• Published in: Circulation (New York, N.Y.) Vol. 111; no. 23; pp. 3112 - 3118
• Main Authors: GUPTA, Himanshu, WHITE, C. Roger, HANDATTU, Shaila, GARBER, David W, DATTA, Geeta, CHADDHA, Manjula, LIJUN DAI, GIANTURCO, Sandra H, BRADLEY, William A, ANANTHARAMAIAH, G. M
• Format: Journal Article
• Language: English
• Published: Hagerstown, MD Lippincott Williams & Wilkins 14.06.2005
• Subjects: Animals; Apolipoproteins E - chemistry; Apolipoproteins E - therapeutic use; Atherosclerosis - drug therapy; Atherosclerosis - prevention & control; Biological and medical sciences; Blood and lymphatic vessels; Cardiology. Vascular system; Cardiovascular system; Cholesterol - blood; Coronary heart disease; Diseases of the peripheral vessels. Diseases of the vena cava. Miscellaneous; Endothelium, Vascular - drug effects; Endothelium, Vascular - pathology; Endothelium, Vascular - physiology; Heart; Hyperlipidemias - drug therapy; Hyperlipidemias - pathology; Inflammation - drug therapy; Investigative techniques of hemodynamics; Investigative techniques, diagnostic techniques (general aspects); Lipid Metabolism, Inborn Errors - drug therapy; Lipids - blood; Male; Medical sciences; Molecular Mimicry; Oxidative Stress - drug effects; Peptide Fragments - chemical synthesis; Peptide Fragments - pharmacology; Peptide Fragments - therapeutic use; Peptides - chemical synthesis; Peptides - pharmacology; Peptides - therapeutic use; Rabbits; Superoxides - analysis; Rabbit; Lipids; Cardiovascular disease; Lipoprotein; Lagomorpha; Metabolism; Cholesterol; Endothelium; Vertebrata; arteriosclerosis; Mammalia; Apolipoprotein E; Animal; Nitric oxide; lipoproteins
• ISSN: 0009-7322; 1524-4539
• DOI: 10.1161/CIRCULATIONAHA.104.497107

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. 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. 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.