It has been shown that several amphipathic helical peptide mimetics of apolipoprotein (apo) A-l inhibitatherosclerosis, improve vascular function, and reduce inflammatory processes. It has also been shown thatco-administration of peptide with statin regresses already-existing atherosclerotic lesions. We hypothesizethat these peptides modify high density lipoprotein (HDL) or recruit phospholipids and apo A-l to form apo Al-containing particles which in turn recruit antiatherogenic enzymes such as paraoxonase-1 (PON-1) and/orplatelet activating-factor acetylhydrolase (PAF-AH). We intend to determine if peptides have antiatheroscleroticproperties in the absence of apo A-l or PON-1. We hypothesize that mimetic peptides act byrecruiting apo A-l into new, more bioactive particles, or by modifying the structure of apo A-l so that it is morebioactive. This may allow it to recruit and/or activate PON-1, resulting in a reduction of atherogenic oxidizedlipids. We will study three peptides: 4F, which is strongly atheroprotective; 3F14, which has no observedatheroprotective properties; and peptide 2F, which is intermediate in its in vitro atheroprotective properties.These peptides differ only in the number of phenylalanine residues on the hydrophobic face. The followingspecific aims are proposed:
Specific Aim 1 : The role of apo A-l in peptide function. The hypothesis to betested is that apo A-l is required for mimetic peptide function, a: We will study the effect of peptides on apoA-l synthesis and secretion, b: We will use atherosclerosis-susceptible mice, either expressing wild-type apoA-l or apo A-l null. We will study the requirement of apo A-l for peptide-mediated functions.
Specific Aim 2 :The role of PON-1 in peptide function. The hypothesis to be tested is that PON-1 is required for mimeticpeptide function, a: Peptide-mediated changes in PON-1 levels and activity will be determined, b: Usingatherosclerosis-susceptible mice expressing PON-1 or PON-1 null, anti-inflammatory properties of thepeptides will be studied.HDL is considered to be protective against atherosclerotic heart disease. We are studying the major proteinof HDL, apo A-l, using small molecules called peptides to mimic the properties of apo A-l. These studies willbe done using mouse models that are susceptible to atherosclerosis. The objective is to better understandhow apo A-l and HDL are protective, and to develop methods to improve those protective properties.
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