title: The apolipoprotein A-I mimetic peptide 4F prevents defects in vascular function in endotoxemic rats.
abstract: High density lipoprotein (HDL) and apolipoprotein A-I (apoA-I) reduce inflammatory responses to lipopolysaccharide (LPS). We tested the hypothesis that the apoA-I mimetic peptide 4F prevents LPS-induced defects in blood pressure and vascular reactivity. Systolic blood pressure (SBP) was measured in rats at baseline and 6 h after injection of LPS (10 mg/kg) or saline vehicle. Subgroups of LPS-treated rats also received 4F (10 mg/kg) or scrambled 4F (Sc-4F). LPS administration reduced SBP by 35% compared with baseline. 4F attenuated the reduction in SBP in LPS-treated rats (17% reduction), while Sc-4F was without effect. Ex vivo studies showed a reduced contractile response to phenylephrine (PE) in aortae of LPS-treated rats (ED(50) = 459 +/- 83 nM) compared with controls (ED(50) = 57 +/- 6 nM). This was associated with nitric oxide synthase 2 (NOS2) upregulation. 4F administration improved vascular contractility (ED(50) = 60 +/- 9 nM), reduced aortic NOS2 protein, normalized plasma levels of NO metabolites, and reduced mortality in LPS-treated rats. These changes were associated with a reduction in plasma endotoxin activity. In vivo administration of (14)C-4F and Bodipy-LPS resulted in their colocalization and retention in the HDL fraction. It is proposed that 4F promotes the localization of LPS to the HDL fraction, resulting in endotoxin neutralization. 4F may thus prevent LPS-induced hemodynamic changes associated with NOS2 induction.
authors.affiliation: Department of Medicine, University of Alabama at Birmingham, Birmingham, AL, USA.
authors.forename: Lijun
authors.initials: L
authors.lastname: Dai
authors.forename: Geeta
authors.initials: G
authors.lastname: Datta
authors.forename: Zhenghao
authors.initials: Z
authors.lastname: Zhang
authors.forename: Himanshu
authors.initials: H
authors.lastname: Gupta
authors.forename: Rakesh
authors.initials: R
authors.lastname: Patel
authors.forename: Jaideep
authors.initials: J
authors.lastname: Honavar
authors.forename: Sarika
authors.initials: S
authors.lastname: Modi
authors.forename: J Michael
authors.initials: JM
authors.lastname: Wyss
authors.forename: Mayakonda
authors.initials: M
authors.lastname: Palgunachari
authors.forename: G M
authors.initials: GM
authors.lastname: Anantharamaiah
authors.forename: C Roger
authors.initials: CR
authors.lastname: White
mesh_terms: D000818:Animals; D016632:Apolipoprotein A-I / Q000235:genetics / Q000494:pharmacology*; D001794:Blood Pressure / Q000187:drug effects* / Q000502:physiology; D001808:Blood Vessels / Q000187:drug effects / Q000502:physiology / Q000503:physiopathology; D008076:Cholesterol, HDL / Q000097:blood; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D019446:Endotoxemia / Q000139:chemically induced / Q000188:drug therapy* / Q000503:physiopathology*; D006439:Hemodynamics / Q000187:drug effects; D006801:Humans; D007213:Indomethacin / Q000494:pharmacology; D008070:Lipopolysaccharides / Q000494:pharmacology; D008297:Male; D009569:Nitric Oxide / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II / Q000037:antagonists & inhibitors / Q000378:metabolism; D009578:Nitrobenzenes / Q000494:pharmacology; D010455:Peptides / Q000235:genetics / Q000494:pharmacology*; D010656:Phenylephrine / Q000494:pharmacology; D011897:Random Allocation; D051381:Rats; D017207:Rats, Sprague-Dawley; D013449:Sulfonamides / Q000494:pharmacology; D014662:Vasoconstrictor Agents / Q000494:pharmacology
chemical_list: D016632:Apolipoprotein A-I; D008076:Cholesterol, HDL; D016861:Cyclooxygenase Inhibitors; D008070:Lipopolysaccharides; D009578:Nitrobenzenes; D010455:Peptides; D013449:Sulfonamides; D014662:Vasoconstrictor Agents; C080955:N-(2-cyclohexyloxy-4-nitrophenyl)methanesulfonamide; D010656:Phenylephrine; D009569:Nitric Oxide; D052247:Nitric Oxide Synthase Type II; C496318:Nos2 protein, rat; D007213:Indomethacin