title: Comparison of anti-endotoxin activity of apoE and apoA mimetic derivatives of a model amphipathic peptide 18A.
abstract: Endotoxemia is a major cause of chronic inflammation, and is an important pathogenic factor in the development of metabolic syndrome and atherosclerosis. Human apolipoprotein E (apoE) and apoA-I are protein components of high-density lipoprotein, which have strong anti-endotoxin activity. Here, we compared anti-endotoxin activity of Ac-hE18A-NH2 and 4F peptides, modified from model amphipathic helical 18A peptide, to mimic, respectively, apoE and apoA-I properties. Ac-hE18A-NH2, stronger than 4F, inhibited endotoxin activity and disaggregated Escherichia coli 055:B5 (wild smooth serotype). Ac-hE18A-NH2 and 4F inhibited endotoxin activity of E. coli 026:B6 (rough-like serotype) to a similar degree. This suggests that Ac-hE18A-NH2 as a dual-domain molecule might interact with both the lipid A and headgroup of smooth LPS, whereas 4F binds lipid A. In C57BL/6 mice, Ac-hE18A-NH2 was superior to 4F in inhibiting the inflammatory responses mediated by E. coli 055:B5, but not E. coli 026:B6. However, in THP-1 cells, isolated human primary leukocytes, and whole human blood, Ac-hE18A-NH2 reduced responses more strongly than 4F to both E. coli serotypes either when peptides were pre-incubated or co-incubated with LPS, indicating that Ac-hE18A-NH2 also has strong anti-inflammatory effects independent of endotoxin-neutralizing properties. In conclusion, Ac-hE18A-NH2 is more effective than 4F in inhibiting LPS-mediated inflammation, which opens prospective clinical applications for Ac-hE18A-NH2.
authors: Department of Medicine, University of Alabama at Birmingham, AL, USA.
authors: Oleg F
authors: OF
authors: Sharifov
authors: Department of Medicine, University of Alabama at Birmingham, AL, USA.
authors: Gaurav
authors: G
authors: Nayyar
authors: Department of Medicine, University of Alabama at Birmingham, AL, USA.
authors: Vladimir V
authors: VV
authors: Ternovoy
authors: Department of Medicine, University of Alabama at Birmingham, AL, USA.
authors: Mayakonda N
authors: MN
authors: Palgunachari
authors: Department of Medicine, University of Alabama at Birmingham, AL, USA.
authors: David W
authors: DW
authors: Garber
authors: Department of Medicine, University of Alabama at Birmingham, AL, USA Department of Biochemistry and Molecular Genetics, University of Alabama at Birmingham, AL, USA.
authors: Gm
authors: G
authors: Anantharamaiah
authors: Department of Medicine, University of Alabama at Birmingham, AL, USA VA Medical Center, Birmingham, AL, USA hgupta@uab.edu.
authors: Himanshu
authors: H
authors: Gupta
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001054:Apolipoproteins A / Q000494:pharmacology*; D001057:Apolipoproteins E / Q000494:pharmacology*; D032701:Biomimetics; D002460:Cell Line; D004731:Endotoxins / Q000037:antagonists & inhibitors*; D005260:Female; D006801:Humans; D066298:In Vitro Techniques; D007962:Leukocytes / Q000187:drug effects; D008070:Lipopolysaccharides / Q000037:antagonists & inhibitors / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D008969:Molecular Sequence Data; D010455:Peptides / Q000494:pharmacology*
chemical_list: D001054:Apolipoproteins A; D001057:Apolipoproteins E; D004731:Endotoxins; D008070:Lipopolysaccharides; D010455:Peptides; C080383:peptide 18A
keywords: Apolipoprotein E mimetic peptide Ac-hE18A-NH2; apolipoprotein A-I mimetic peptide L-4F; endotoxin; inflammation; lipopolysaccharide