All ETDs from UAB

Advisory Committee Chair

G M Anatharamaiah

Advisory Committee Members

David W Garber

C Roger White

Jose R Fernandez

Yuchang Fu

W Timothy Garvey

Document Type

Dissertation

Date of Award

2012

Degree Name by School

Doctor of Philosophy (PhD) School of Health Professions

Abstract

Despite major advances in diagnosis and treatment, coronary artery disease (CAD) is still the number one cause of morbidity and mortality in United States. An ideal treatment for lipid-mediated inflammatory disorders would not only reduce plasma cholesterol dramatically but also improve high density lipoproteins (HDL) function. Apolipoprotein E (apo E), a protein component of HDL and very low density lipoprotein (VLDL), is necessary for the receptor mediated hepatic uptake of apolipoprotein-B (apo B) containing remnant lipoproteins and also possesses strong anti-inflammatory properties. We hypothesized that a synthetic dual domain apo E mimetic peptide, Ac-hE18A-NH2 (a 28-residue peptide) containing receptor binding region (141-150) from human apo E covalently linked to a well-studied lipid binding amphipathic helical peptide18A will inhibit atherosclerosis and improve HDL due to its anti-inflammatory properties and its ability to clear atherogenic lipoproteins, analogous to full length apoE (299 amin oacids in length). Administration of Ac-hE18A-NH2 into dyslipidemic animal models resulted in a dramatic reduction in plasma cholesterol levels via binding to heparan sulfate proteoglycans (HSPG), while no reduction was seen in plasma cholesterol levels in animals injected with either saline or a control peptide (Ac-nhE18A-NH2 , obtained by covalently linking 151-160 region of apoE to 18A). Administration of Ac-hE18A-NH2 three times a week for six weeks to apo E null mice improved paraoxonase-1 (PON-1) activity, a marker for improved HDL function, and inhibited LDL-induced monocyte chemotaxis and atherosclerotic lesion progression. Ac-hE18A-NH2 was more effective than 4F, a well studied apolipoprotein A-I (apo A-I) mimetic peptide, in inhibiting atherosclerosis in an animal model. Recent investigations comparing this peptide Ac-hE18A-NH2 to the 18-residue single domain apoE mimetic peptide mR18L capable of reducing plasma cholesterol in LDL-R null mice fed a Western diet, showed while peptides were comparable in their ability to reduce plasma cholesterol; the peptide Ac-hE18A-NH2 was significantly more effective in reducing lesion. In conclusion, results of these investigations show that the 28 residue peptide Ac-hE18A-NH2 mimics apolipoprotein E in cholesterol reducing and anti-inflammatory properties and may be an ideal agent to treat lipid-mediated disorders worthy of clinical trials in humans.

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