Systemic deficiency of mouse arachidonate 15‐lipoxygenase induces defective erythropoiesis and transgenic expression of the human enzyme rescues this phenotype

Abstract

Oxidative stress, 1 which has been implicated in the pathogenesis of inflammatory, hyperproliferative, and neurodegenerative diseases, 2-4 is defined as an imbalance of the cellular redox equilibrium. At low concentrations, reactive oxygen species (ROS) function as second messengers 5 and are essential for proper cell function. In contrast, at higher levels ROS induce cellular malfunction and even cell death, such as apoptosis and/or necroptosis. 6,7 Usually, the intracellular redox homeostasis is well balanced and 15-lipoxygenase (ALOX15) plays an important role in the regulation of this equilibrium. 8,9 However, in mammals ALOX isoforms have also been implicated in more

Embryonal erythropoiesis and aging exploit ferroptosis

“…Indeed, 15-lipoxygenase (LOX), which directly oxidizes phosphatidylethanolamines to generate lipid hydroperoxides, is highly expressed in reticulocytes [ 48 , 49 ]. Whereas an early work found that erythrocyte and reticulocyte count were normal in 12/15-LOX knockout mice [ 50 ], a recent study revealed that the blood of 15-LOX -/- mice involved an increased proportion of structurally modified erythrocytes, although the structural and functional differences between wild-type and 15-LOX -/- erythrocytes are not very profound [ 51 ]. Erythropoietin reportedly affects enucleation negatively in association with cellular ROS [ 52 ].…”

Male Knock-in Mice Expressing an Arachidonic Acid Lipoxygenase 15B (Alox15B) with Humanized Reaction Specificity Are Prematurely Growth Arrested When Aging

“…Osmotic resistance of erythrocytes —To assess the resistance of the red blood cells for osmotic stress, we followed the experimental protocol described before [ 25 ]. For this purpose, 2 μL of blood was diluted in 200 μL phosphate buffer (pH 7.4) containing NaCl at different concentrations (0–0.85%) and the cells were incubated for 30 min at room temperature.…”

Regulation of Tissue Inflammation by 12-Lipoxygenases

“…With respect to therapeutic targeting, several inhibitors are at the developmental stages for specific targeting of 12-LOXs [ 146 ]. It is intriguing that in mouse models, depletion or inactivation of 12-LOX prevents major disease development and/or progression, though it will be important to determine if there are deleterious global effects of inactivation of the 12-LOXs, as the Alox15 null mice show hematopoietic defects leading to a myeloproliferative disorder as well as defective erythropoiesis [ 147 , 148 ]. Therefore, it is critical to follow these animal models for extended periods to ensure that there are no long-term adverse effects of 12-LOX inhibition.…”