Metabolomic Profiling of Plasma and Erythrocytes in Sickle Mice Points to Altered Nociceptive Pathways

Abstract

Few data-driven metabolomic approaches have been reported in sickle cell disease (SCD) to date. We performed a metabo-lipidomic study on the plasma and red blood cells of a steady-state mouse model carrying the homozygous human hemoglobin SS, compared with AS and AA genotypes. Among the 188 metabolites analyzed by a targeted quantitative metabolomic approach, 153 and 129 metabolites were accurately measured in the plasma and red blood cells, respectively. Unsupervised PCAs (principal component analyses) gave good spontaneous discrimination between HbSS and controls, and supervised OPLS-DAs (orthogonal partial least squares-discriminant analyses) provided highly discriminant models. These models confirmed the well-known deregulation of nitric oxide synthesis in the HbSS genotype, involving arginine deficiency and increased levels of dimethylarginines, ornithine, and polyamines. Other discriminant metabolites were newly evidenced, such as hexoses, alpha-aminoadipate, serotonin, kynurenine, and amino acids, pointing to a glycolytic shift and to the alteration of metabolites known to be involved in nociceptive pathways. Sharp remodeling of lysophosphatidylcholines, phosphatidylcholines, and sphingomyelins was evidenced in red blood cells. Our metabolomic study provides an overview of the metabolic remodeling induced by the sickle genotype in the plasma and red blood cells, revealing a biological fingerprint of altered nitric oxide, bioenergetics and nociceptive pathways.

In vivoevaluation of the effect of sickle cell hemoglobin S, C and therapeutic transfusion on erythrocyte metabolism and cardiorenal dysfunction

“…For example, dysregulation of arginine metabolism 18 may constrain nitric oxide biosynthesis through substrate competition of arginase with endothelial nitric oxide synthase, thus limiting the vasodilatory capacity in SCD, with direct upstream regulatory effects on vaso-occlusive crisis, cardiovascular, cerebral and renal complications of SCD. [19][20][21][22][23][24] While most metabolomics studies in SCD have focused on plasma, a limited set of studies has investigated the RBC compartment. 11,20,22,25,26 These studies -always limited in sample size owing to technical constraints -suggested that depletion of glutamine, a precursor to glutathione, is a potential contributor to the increased susceptibility to hemolysis of the sickle erythrocyte, 26 owing to oxidant damage to proteins and lipids.…”

Plasma Levels of Acyl-Carnitines and Carboxylic Acids Correlate With Cardiovascular and Kidney Function in Subjects With Sickle Cell Trait

“…In addition, SCT has been established as a modest risk factor of venous thromboembolism among African Americans, but this risk is 1.5 to 2.0 fold greater in those with SCT compared to those without ( Austin et al, 2007 ; Folsom et al, 2015 ). While the mechanisms of metabolic reprogramming have been extensively investigated in humans ( Darghouth et al, 2011 ; Zhang et al, 2011 ; Wu et al, 2016 ) and mouse models of SCD ( Dembélé et al, 2020 ), to the best of the authors’ knowledge, literature is scarce or non-existent in the context of SCT, which is the focus of the present study.…”

In vivo evaluation of the effect of sickle cell hemoglobin S, C and therapeutic transfusion on erythrocyte metabolism and cardiorenal dysfunction

“…For example, dysregulation of arginine metabolism 19 may constrain nitric oxide biosynthesis through substrate competition of arginase with endothelial nitric oxide synthase, thus limiting the vasodilatory capacity in SCD, with direct upstream regulatory effects on vaso-occlusive crisis, cardiovascular, cerebral and renal complications of SCD. [20][21][22][23][24][25] While most metabolomics studies in SCD have focused on plasma, a limited set of studies has investigated the RBC compartment. 12,21,23,26,27 These studies-always limited in sample size owing to technical constraints-suggested that depletion of glutamine, a precursor to glutathione, is a potential contributor to the increased susceptibility to hemolysis of the sickle erythrocyte, 27 owing to oxidant damage to proteins and lipids.…”