The Impact of Selenium Deficiency on a Sickle Cell Disease Mouse Model

Abstract

Sickle cell disease (SCD) is caused by a mutation in the β-globin gene resulting in a disease that affects more than 100,000 Americans and millions worldwide. Though pain is the hallmark of SCD, patients also suffer damage to most organ systems. Sickle cell hemoglobin (HbS) polymerization occurs when deoxygenated, rendering red blood cells rigid and fragile. Production of excessive reactive oxygen species (ROS) and intracellular hypoxia in RBCs further accelerates the pathology associated with SCD. Recently, vaso-occlusive crisis (VOC) and organ damage were established to be strongly associated with oxidative stress in RBCs. This occurs when there is an increase in oxidants that exceeds the cellular anti-oxidant defenses. Excessive ROS can trigger a cascade of oxidative reactions that damage membrane lipids, and essential enzymatic antioxidants such as GPx-1, ultimately leading to hemolysis and multi-organ dysfunction. ROS generation in RBCs of SCD patients is due to factors such as HbS auto-oxidation and potentially aberrant mitochondrial function. We recently determined that red blood cells obtained from SCD mice and SCD patients retain their mitochondria compared to control subjects. Mitochondria retained SCD RBCs are also associated with elevated levels of ROS and hemolysis. Oxidative stress in the RBCs of SCD patients may be elevated by lower levels of antioxidant proteins such as the selenium-dependent enzyme GPX1. GPX1 was first described as an enzyme capable of protecting hemoglobin from ROS and has been reported to be lower in the RBCs in SCD. Selenium levels are lower among African Americans in the Chicago area and elsewhere. In this regard, it is notable that in the United States, African Americans represent the majority of those with SCD. To investigate the relationship between selenium levels and SCD, we have utilized a mouse model of SCD to examine the impact of a reduced intake of selenium on parameters associated with SCD pathology. SCD mice on a selenium-deficient diet (<0.01 mg/kg diet) were compared to mice fed with a selenium-adequate diet (0.1mg/kg). SCD mice in the selenium-deficient group exhibited an increase in mitochondria retaining RBCs (Se deficient: 26%±6.9%, n=3 vs. Se adequate: 5 % ± 3.5%, n=3, p<0.01), reduced Hb levels (Se deficient 5.7± 0.17 g/dl, n=3 vs. Se adequate 7.0± 0.83 g/dl, n=4 p<0.05), and an increased RBC oxygen consumption rate (OCR). These results support the hypothesis that low selenium status likely results in reduced levels of anti-oxidant selenoproteins and enhanced SCD severity. Disclosures Lavelle: Global Blood therapeutics: Research Funding.

Metabolic signatures of cardiorenal dysfunction in plasma from sickle cell patients, as a function of therapeutic transfusion and hydroxyurea treatment

“…56 It is interesting to note that mitochondrial DNA and RNA (e.g., in the context of aging) have been reported to contribute to activation of the cGAS-STING responses. 57 Since mature sickle RBCs have been reported to contain up to 5-6 residual mitochondria per cell, 58,59 in light of the elevated degree of sickle RBC hemolysis, it is tempting to speculate that the elevated kynurenine levels as a function of high degree of hemolysis reported here participate in a similar circulating mitochondrial DNA sensing cascade, which could pave the way for potential novel therapeutic interventions. Finally, it is worth noting that elevation of kynurenine and indoles subtracts a substrate for the synthesis of serotonin, which is an essential component of platelet dense granules 60 and a neurotransmitter that could contribute to counteracting nociceptive signaling.…”

Selenium supplementation may improve COVID-19 survival in sickle cell disease

“…[10] Selenium status is inversely associated with haemolysis in SCD, and may both inhibit haemolysis and enhance erythropoiesis in SCD. [3,11] Selenium is required for the actions of both vitamin D and dexamethasone. [12,13] Selenite infusion is safe, including in critically ill and dialysis patients, and selenium supplementation has had favourable effects in other RNA virus infections.…”

“…SARS-CoV-2 may infect cells in bone marrow, supressing red blood cell formation (10) . Se status is inversely associated with haemolysis in SCD and may both inhibit haemolysis and enhance erythropoiesis in SCD (3,11) .Se is required for the actions of both vitamin D and dexamethasone (12,13) . Se infusion is safe, including in critically ill and dialysis patients, and Se supplementation has had favourable effects in other RNA virus infections (14)(15)(16) .It should be noted that vitamin C and Mg are also commonly deficient nutrients and are required for the activation of vitamin D 3 by hydroxylation (17)(18)(19) .…”

“…SARS-CoV-2 may infect cells in bone marrow, supressing red blood cell formation (10) . Se status is inversely associated with haemolysis in SCD and may both inhibit haemolysis and enhance erythropoiesis in SCD (3,11) .…”

Sickle red blood cell‐derived extracellular vesicles activate endothelial cells and enhance sickle red cell adhesion mediated by von Willebrand factor

“…19,20 REVs made up the most prevalent subtype, and correlated with haemolysis, oxygen saturation, pulmonary systolic pressure and mortality. 21 REVs in SCD (SS REVs) may be produced through accelerated ageing of RBCs during oxygenation/deoxygenation cycles, 16 under the influence of stress factors, 4,[22][23][24] or during haemolysis in capillary beds. SS REVs are reported to have increased phosphatidylserine (PS) expression on their surface, 12 as well as to contain haeme, Hb, oxidised Hb, ferryl Hb, and microRNAs.…”