title: Inhibition of myeloperoxidase decreases vascular oxidative stress and increases vasodilatation in sickle cell disease mice.
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.
authors: Departments of Surgery, Milwaukee, WI 53226.
authors: Hao
authors: H
authors: Zhang
authors: Hao
authors: H
authors: Xu
authors: Dorothee
authors: D
authors: Weihrauch
authors: Deron W
authors: DW
authors: Jones
authors: Xigang
authors: X
authors: Jing
authors: Yang
authors: Y
authors: Shi
authors: David
authors: D
authors: Gourlay
authors: Keith T
authors: KT
authors: Oldham
authors: Cheryl A
authors: CA
authors: Hillery
authors: Kirkwood A
authors: KA
authors: Pritchard
mesh_terms: D000755:Anemia, Sickle Cell / Q000201:enzymology / Q000378:metabolism / Q000503:physiopathology*; D000818:Animals; D001808:Blood Vessels / Q000187:drug effects* / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D004305:Dose-Response Relationship, Drug; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005260:Female; D006801:Humans; D006997:Hypochlorous Acid / Q000378:metabolism; D019041:L-Selectin / Q000737:chemistry / Q000378:metabolism; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D009842:Oligopeptides / Q000494:pharmacology; D018384:Oxidative Stress / Q000187:drug effects*; D009195:Peroxidase / Q000037:antagonists & inhibitors* / Q000097:blood; D012995:Solubility; D014664:Vasodilation / Q000187:drug effects*
chemical_list: D004791:Enzyme Inhibitors; D009842:Oligopeptides; D019041:L-Selectin; D006997:Hypochlorous Acid; D009195:Peroxidase
keywords: L-selectin; aorta; chlorotyrosine; endothelial cells; facialis artery; liver; malondialdehyde; polymorphonuclear cells
references: Blood. 2008 Sep 15;112(6):2529-38
references: 18579795
references: Am J Med Sci. 1987 Oct;294(4):253-7
references: 3661621
references: Free Radic Biol Med. 2002 Oct 1;33(7):1010
references: 12361810
references: Free Radic Biol Med. 2007 Dec 1;43(11):1469-83
references: 17964418
references: J Leukoc Biol. 1999 Sep;66(3):411-5
references: 10496310
references: Clin J Sport Med. 2004 Nov;14(6):354-6
references: 15523207
references: J Lipid Res. 2013 Nov;54(11):3016-29
references: 23883583
references: Am J Trop Med Hyg. 1993 Dec;49(6):799-803
references: 8279646
references: Blood. 2003 May 15;101(10):3953-9
references: 12543857
references: Proc Natl Acad Sci U S A. 2005 Jan 11;102(2):431-6
references: 15625114
references: Am J Physiol Heart Circ Physiol. 2002 Jan;282(1):H122-30
references: 11748055
references: Circ Res. 2005 Nov 25;97(11):1190-7
references: 16224061
references: Blood. 2000 Oct 1;96(7):2451-9
references: 11001897
references: Blood. 1996 May 15;87(10):4440-7
references: 8639806
references: Cell Mol Biol (Noisy-le-grand). 2004 Feb;50(1):95-105
references: 15040433
references: Blood. 2012 Jul 19;120(3):636-46
references: 22661702
references: Am J Physiol Lung Cell Mol Physiol. 2004 Apr;286(4):L705-14
references: 12972407