title: Anti-inflammatory and recycling properties of an apolipoprotein mimetic peptide, Ac-hE18A-NH(2).
abstract: Apolipoprotein E (apoE) exerts prominent anti-inflammatory effects and undergoes recycling by target cells. We previously reported that the peptide Ac-hE18A-NH(2), composed of the receptor binding domain (LRKLRKRLLR) of apoE covalently linked to the Class A amphipathic peptide 18A, dramatically lowers plasma cholesterol and lipid hydroperoxides and enhances paraoxonase activity in dyslipidemic animal models. The objective of this study was to determine whether this peptide, analogous to apoE, exerts anti-inflammatory effects and undergoes recycling under in vitro conditions. Pulse chase studies using [(125)I]-Ac-hE18A-NH(2) in THP-1 derived macrophages and HepG2 cells showed greater amounts of intact peptide in the cells at later time points indicating recycling of the peptide. Ac-hE18A-NH(2) induced a 2.5-fold increase in prebeta-HDL in the conditioned media of HepG2 cells. This effect persisted for 3 days after removal of the peptide from culture medium. Ac-hE18A-NH(2) also induced the secretion of cell surface apoE from THP-1 macrophages. In addition, the peptide increased cholesterol efflux from THP-1 cells by an ABCA1 independent mechanism. Moreover, Ac-hE18A-NH(2) inhibited LPS-induced vascular cell adhesion molecule-1 (VCAM-1) expression, and reduced monocyte adhesion in human umbilical vein endothelial cells (HUVECs). It also reduced the secretion of interleukin-6 (IL-6) and monocyte chemoattractant protein-1 (MCP-1) from THP-1 macrophages even when administered post-LPS and abolished the 18-fold increase in LPS-induced mRNA levels for MCP-1 in THP-1 cells. Taken together, these results suggest that addition of the putative apoE receptor-domain to the Class A amphipathic peptide 18A results in a peptide that, similar to apoE, recycles, thus enabling the potentiation and prolongation of its anti-atherogenic and anti-inflammatory effects. Such a peptide has great potential as a therapeutic agent in the management of atherosclerosis and other inflammatory diseases.
authors: Department of Medicine, Atherosclerosis Research Unit, Division of Gerontology, Geriatrics and Palliative Medicine, University of Alabama at Birmingham, 1808 Seventh Avenue South, Birmingham, AL 35294, USA. gdatta@uab.edu
authors: Geeta
authors: G
authors: Datta
authors: C Roger
authors: CR
authors: White
authors: Nassrin
authors: N
authors: Dashti
authors: Manjula
authors: M
authors: Chaddha
authors: Mayakonda N
authors: MN
authors: Palgunachari
authors: Himanshu
authors: H
authors: Gupta
authors: Shaila P
authors: SP
authors: Handattu
authors: David W
authors: DW
authors: Garber
authors: G M
authors: GM
authors: Anantharamaiah
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D002478:Cells, Cultured; D053442:High-Density Lipoproteins, Pre-beta / Q000096:biosynthesis / Q000187:drug effects; D006801:Humans; D007249:Inflammation / Q000517:prevention & control; D008074:Lipoproteins / Q000494:pharmacology*; D010446:Peptide Fragments / Q000494:pharmacology*; D010455:Peptides / Q000378:metabolism; D011817:Rabbits; D013997:Time Factors
chemical_list: C478448:Ac-hE18A-NH(2); D000893:Anti-Inflammatory Agents; D053442:High-Density Lipoproteins, Pre-beta; D008074:Lipoproteins; D010446:Peptide Fragments; D010455:Peptides