An apoA-I mimetic peptide containing a proline residue has greater in vivo HDL binding and anti-inflammatory ability than the 4F peptide

Geoffrey D. Wool, Tomas Vaisar, Catherine A. Reardon, and Godfrey S. Getz

Department of Pathology, University of Chicago, Chicago, IL 60637-1470

Corresponding Author: g-getz{at}uchicago.edu

Modifying apoA-I mimetic peptides to include a proline-punctuated a-helical repeat increases their anti-inflammatory properties as well as allows better mimicry of full-length apoA-I function. This study compares the following mimetics, either acetylated (ac) or biotinylated (b): 4F (18mer) and 4F-proline-4F (37mer, Pro). b4F interacts with both mouse HDL and LDL in vitro. b4F in vivo plasma clearance kinetics are not affected by mouse HDL status. Administration of biotinylated peptides to mice demonstrates that b4F does not associate with lipoproteins smaller than LDL in vivo, though it does associate with fractions containing free hemoglobin. In contrast, bPro specifically interacts with HDL. b4F and bPro show opposite binding responses to HDL by surface plasmon resonance (SPR). Administration of acPro to apoE-/- mice significantly decreases plasma SAA levels, while ac4F does not have this ability. In contrast to previous reports which inferred that 4F associates with HDL in vivo, we systematically examined this potential interaction and demonstrated that b4F does not interact with HDL in vivo but rather elutes with hemoglobin-containing plasma fractions. bPro, however, specifically binds to mouse HDL in vivo. In addition, the number of amphipathic a-helices and their linker influences the anti- inflammatory effects of apoA-I mimetic peptides in vivo.

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