Abstract As a negative risk factor for atherosclerosis, both the level and functional properties of HDL are important. Therapeutics based on infusion of apoA-I, the major apoprotein on HDL, or apoA-I mimetic peptides have been used in a limited number of studies. The apoA-I mimetic peptides have physiochemical properties similar to the amphipathic -helices in apoA-I. The most extensively studied peptide, 4F, mimics a single repeat structure in apoA-I. This peptide has been shown to be anti-inflammatory in a variety of disease settings involving inflammation, both chronic inflammation such as atherosclerosis and acute inflammation. A variety of potential mechanisms have been proposed by which the peptide may exert its protection. One potential link between atherosclerosis and other inflammatory disorders is oxidized lipids. 4F has been shown to bind to oxidized phospholipids with high affinity. In this proposal we set out approaches to determine how important is this property of 4F in accounting for its efficacy in vivo. It is not clear if 4F is the 'ideal' peptide since apoA-I has multiple helices, many of which are separated by proline residues. We have shown that the monomer 4F and tandem 4F peptides have different in vivo and in vitro properties, including the ability to associate with HDL. One property that both share is the ability to promote the production of antibodies to oxidized phospholipids. The major goals of this proposal are - a) to compare the in vivo efficacy of monomeric 4F mimetic peptide and tandem (4F Pro4F) peptides in the treatment of acute septic inflammation (cecal ligation and puncture model) and atherosclerosis; b) to ascertain if the efficacy of these peptides is dependent upon their interaction with HDL by comparing effects in apoE-/-apoA-I-/- mice with apoE-/- mice; c) and to learn which putative mechanism of action of these peptides is most important for their in vivo anti-inflammatory and anti-atherogenic efficacy. The mechanisms upon which we will focus in this proposal are the sequestration of oxidized lipids and the stimulation of the production of antibodies to oxidized phospholipids. This will be studied using mice deficient in the production of oxidized lipids or reactive oxygen species using three models in which oxidation pathways are interdicted and mice deficient in the ability to produce antibodies. .