Inhibition of myeloperoxidase decreases vascular oxidative stress and increases vasodilatation in sickle cell disease mice

Abstract

Although polymorphonuclear neutrophils (PMN) are well recognized for playing important roles in infl ammation in sickle cell disease (SCD), direct evidence linking myeloperoxidase (MPO) to impaired vascular endothelial cell (EC) function in SCD remains lacking. Over the last 25 years, only a handful of studies have been published suggesting that MPO may be involved. One of the fi rst reports, published in 1986, showed that vaso-occlusive crises increased PMN stickiness, an index of activation, in SCD patients ( 1 ). In 1993, plasma levels of MPO and C3d were reported to be higher in SCD patients than in controls, and these biomarkers inversely correlated with red cell hemoglobin ( 2 ). In 1996, PMN were shown to interact directly with the sickle red blood cell (RBC), and this interaction notably enhanced PMN activation ( 3 ). Later in 2002, it was reported that activated PMN increased sickle RBC retention in isolated rat lungs ( 4 ) and that MPO and 3-nitrotyrosine colocalized in sections of lungs from patients who died from complications associated with SCD ( 5 ). Evidence that stress increases MPO in SCD comes from studies showing that exercise induced a dual increase in plasma MPO and percentage of sickled cells in SCD patients ( 6 ). Finally, evidence linking the coagulation pathway to infl ammation in sickle cell anemia comes from studies showing that inhibiting tissue factor decreased MPO in the lungs of SCD mice ( 7 ). Although these reports and others ( 8-10 ) provide strong support for the idea that PMN activation and MPO play important roles in SCD, 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 de-

Inhibition of myeloperoxidase at the peak of experimental autoimmune encephalomyelitis restores blood–brain barrier integrity and ameliorates disease severity

“…Of importance, we have demonstrated that KYC “competitively inhibits” MPO by outcompeting MPO substrates such as Cl − for the active site and in so doing accelerates H 2 O 2 consumption (Zhang et al 2013a). The importance of this property is underscored by our report showing that KYC decreased the accumulation of MPO in aortas isolated from sickle cell mice to the same levels as control mice (Zhang et al 2013b). In addition, KYC increased endothelial cell-dependent vasodilation in sickle cell mice by nearly 2-fold to ~60% of control levels (Zhang et al 2013b).…”

Oxidative stress and phosphatidylserine exposure in red cells from patients with sickle cell anaemia

“…SCA is associated with increased oxidative stress, neutrophil leucocytosis and vascular endothelial dysfunction, all of which are also associated with increased PS exposure (Jain, 1985; Hebbel, 1991; Kuypers, 1998; Mutze et al , 2003; Banerjee & Kuypers, 2004; Zhang et al , 2013). Recent reviews have reinforced the view that ROS are actively involved in lipid scrambling in SCA (Cimen, 2008; Mohanty et al , 2014; Voskou et al , 2015), with limited experimental evidence supporting this assumption.…”

“…This is particularly significant in diseases such as SCA in which vascular oxidative stress is increased (Rice‐Evans et al , 1986) with accumulations of highly reactive oxygen species (ROS) including the superoxide anion, hydrogen peroxide and the hydroxyl radical (Sies, 1997; Chirico & Pialoux, 2012; Voskou et al , 2015). Myeloperoxidase released from activated neutrophils may also add to oxidant challenge in SCA, through production of hypochlorous acid (HOCl) from hydrogen peroxide (Vissers et al , 1994; Mutze et al , 2003; Zhang et al , 2013). Thiol oxidation has also been associated with both inhibition of the flippase and stimulation of the scramblase (Morrot et al , 1989; Connor & Schroit, 1990; Devaux & Zachowski, 1994; Martin & Jesty, 1995; de Jong & Kuypers, 2006).…”

VPO1 Modulates Vascular Smooth Muscle Cell Phenotypic Switch by Activating Extracellular Signal‐regulated Kinase 1/2 (ERK 1/2) in Abdominal Aortic Aneurysms

“…3‐Cl‐tyr levels were evaluated by Western blot. After blotting for 3‐chlorotyrosine, 3 immunospecific bands of molecular weight 43, 55, and 72 kDa were visualized 15, 16…”