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.
Highlights
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
Our studies show that KYC decreases soluble L-selectin, oxidative stress, and liver injury and that it improves vascular EC function in sickle cell disease (SCD) mice
Our findings demonstrate that MPO plays a central role in the mechanisms by which SCD impairs vascular function
Summary
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. Evidence linking the coagulation pathway to inflammation in sickle cell anemia comes from studies showing that inhibiting tissue factor decreased MPO in the lungs of SCD mice [7] These reports and others [8,9,10] provide strong support for the idea that PMN activation and MPO play important roles in SCD, Abbreviations: 3-ClTyr, 3-chlorotyrosine; 3-NO2Tyr, 3-nitrotyrosine; AA, control; ALT, alanine transaminase; EC, endothelial cell; eNOS, endothelial nitric oxide synthase; H&E, hematoxylin and eosin; KYC, N-acetyl-lysyltyrosylcysteine-amide; L-NAME, L-nitroargininemethylester; MDA, malondialdehyde; MPO, myeloperoxidase; NO, nitric oxide; PMN, polymorphonuclear neutrophil; SCD, sickle cell disease; sL-selectin, soluble L-selectin. Our studies show that KYC decreases soluble L-selectin (sL-selectin), oxidative stress, and liver injury and that it improves vascular EC function in SCD mice
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