Inhibition of myeloperoxidase decreases vascular oxidative stress and increases vasodilatation in sickle cell disease mice. J Lipid Res 2013 Nov;54(11):3009-15
Date
08/21/2013Pubmed ID
23956444Pubmed Central ID
PMC3793605DOI
10.1194/jlr.M038281Scopus ID
2-s2.0-84886071622 (requires institutional sign-in at Scopus site) 34 CitationsAbstract
Activated leukocytes and polymorphonuclear neutrophils (PMN) release myeloperoxidase (MPO), which binds to endothelial cells (EC), is translocated, and generates oxidants that scavenge nitric oxide (NO) and impair EC function. To determine whether MPO impairs EC function in sickle cell disease (SCD), control (AA) and SCD mice were treated with N-acetyl-lysyltyrosylcysteine-amide (KYC). SCD humans and mice have high plasma MPO and soluble L-selectin (sL-selectin). KYC had no effect on MPO but decreased plasma sL-selectin and malondialdehyde in SCD mice. MPO and 3-chlorotyrosine (3-ClTyr) were increased in SCD aortas. KYC decreased MPO and 3-ClTyr in SCD aortas to the levels in AA aortas. Vasodilatation in SCD mice was impaired. KYC increased vasodilatation in SCD mice more than 2-fold, to ∼60% of levels in AA mice. KYC inhibited MPO-dependent 3-ClTyr formation in EC proteins. SCD mice had high plasma alanine transaminase (ALT), which tended to decrease in KYC-treated SCD mice (P = 0.07). KYC increased MPO and XO/XDH and decreased 3-ClTyr and 3-nitrotyrosine (3-NO₂Tyr) in SCD livers. These data support the hypothesis that SCD increases release of MPO, which generates oxidants that impair EC function and injure livers. Inhibiting MPO is an effective strategy for decreasing oxidative stress and liver injury and restoring EC function in SCD.
Author List
Zhang H, Xu H, Weihrauch D, Jones DW, Jing X, Shi Y, Gourlay D, Oldham KT, Hillery CA, Pritchard KA JrAuthors
David M. Gourlay MD Chief, Professor in the Surgery department at Medical College of WisconsinXi-Gang Jing Research Scientist I in the Pediatrics department at Medical College of Wisconsin
Kirkwood A. Pritchard PhD Professor in the Surgery department at Medical College of Wisconsin
Dorothee Weihrauch DVM, PhD Research Scientist II in the Anesthesiology department at Medical College of Wisconsin
MESH terms used to index this publication - Major topics in bold
Anemia, Sickle CellAnimals
Blood Vessels
Dose-Response Relationship, Drug
Endothelial Cells
Enzyme Inhibitors
Female
Humans
Hypochlorous Acid
L-Selectin
Liver
Male
Mice
Oligopeptides
Oxidative Stress
Peroxidase
Solubility
Vasodilation