Patients with sickle cell disease presented dysregulated plasma Rb/K ratio and Gamma-glutamyl cycle in red blood cells

Abstract Patients suffering from sickle cell disease (SCD) present with multifactorial pathology, and a detailed understanding of it may help to develop novel therapeutics. In this study, the plasma elemental (24Mg, 44Ca, 57Fe, 63Cu, 66Zn, 77Se, 85Rb, 208Pb, and 39K) levels of SCD patients (n=10, male: 50%) and control groups (trait and healthy; n=10 each; male: 50%) were profiled using inductively coupled plasma mass spectrometry (ICP-MS). Additionally, comparative global erythrocyte metabolomics of SCD (n=5, male:100%) and healthy controls (n=5, male:100%) were carried out using liquid chromatography-mass spectrometry (LC-MS). SCD patients had higher plasma 24Mg, 44Ca, 66Zn, 208Pb, and 39K levels and lower levels of 57Fe, 77Se, and 85Rb compared to controls. These changes in elemental levels, with a decreased Rb/K ratio in the SCD group, may explain the observed frequent hemolysis and severe dehydration with oxidative stress in patients. Mass spectrometry analysis of red blood cells (RBCs of SCD (n=5) and healthy controls (n=5) identified 442 unique metabolic features which separately clustered both the study groups in principal component analysis (PCA). A set of 136 features showed differential (p<0.05; log2fold change>±1) regulation and was involved in D-glutamine/D-glutamate, sphingolipid, arginine biosynthesis, glutathione and glycine, serine and threonine metabolism. Interestingly, higher pyroglutamic acid levels were observed in the sickle shaped-RBCs indicating a perturbed gamma-glutamyl pathway in SCD patients. Supplementation of the depleted trace metals and targeting the perturbed metabolic pathways in the RBCs of SCD patients may provide avenues for the development of alternate therapeutics. Graphical abstractmedrxiv;2023.05.17.23290113v2/UFIG1F1ufig1