The apolipoprotein A-I mimetic peptide 4F prevents defects in vascular function in endotoxemic rats.
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.
Dai
Lijun
L
Department of Medicine, University of Alabama at Birmingham, Birmingham, AL, USA.
Datta
Geeta
G
Zhang
Zhenghao
Z
Gupta
Himanshu
H
Patel
Rakesh
R
Honavar
Jaideep
J
Modi
Sarika
S
Wyss
J Michael
JM
Palgunachari
Mayakonda
M
Anantharamaiah
G M
GM
White
C Roger
CR
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
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