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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

08/21/2013

Pubmed ID

23956444

Pubmed Central ID

PMC3793605

DOI

10.1194/jlr.M038281

Scopus ID

2-s2.0-84886071622   19 Citations

Abstract

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 Jr

Authors

David M. Gourlay MD Chief, Professor in the Surgery department at Medical College of Wisconsin
Keith T. Oldham MD Professor in the Surgery department at Medical College of Wisconsin
Kirkwood A. Pritchard PhD Professor in the Surgery department at Medical College of Wisconsin
Dorothee Weihrauch DVM, PhD Professor in the Anesthesiology department at Medical College of Wisconsin




MESH terms used to index this publication - Major topics in bold

Anemia, Sickle Cell
Animals
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
jenkins-FCD Prod-400 0f9a74600e4e79798f8fa6f545ea115f3dd948b2