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.
Highlights
Sickle cell disease (OMIM #603903) is the most common autosomal recessive disorder worldwide, caused by the homozygous pathogenic variant p.(Val6Glu) in the gene encoding the β-globin chain of hemoglobin (HBB) [1]
Among the 188 metabolites analyzed by the kit, 153 were accurately measured in the plasma, including the hexoses (n = 1, sum of), amino acids (n = 21), biogenic amines (n = 15), carnitine, acylcarnitines (n = 12), sphingomyelins (n = 15), phosphatidylcholines (n = 75) and lysophosphatidylcholines (n = 13)
Our metabolomic signature is in full activity, as the ornithine itself is a substrate for polyamines, agreement with this metabolic shift, showing decreased concentration in the HbSS genotype of arginine proline and glutamate synthesis
Summary
Sickle cell disease (OMIM #603903) is the most common autosomal recessive disorder worldwide, caused by the homozygous pathogenic variant p.(Val6Glu) in the gene encoding the β-globin chain of hemoglobin (HBB) [1]. The increased tendency of hemoglobin S to polymerize and aggregate, enhanced in circumstances favoring hypoxia and hemoglobin deoxidation, increases the erythrocyte rigidity, producing the “sickled” red blood cells (RBC) with altered rheological properties. This leads to hemolysis, anemia and painful life-threatening vaso-occlusive crises with deleterious consequences in the organs, such as pulmonary hypertension, ischemic stroke, cutaneous leg ulceration, priapism, and renal insufficiency. Metabolomics, the generation of metabolic biochemistry, is a powerful hypothesis-free approach highlighting the biological imprinting of the diseases. Among the 89 metabolites identified, 31 exhibited significantly modified concentrations, revealing an involvement of glycolysis, pentose phosphate, glutathione, ascorbate, amino acids, polyamines, carnitine, and creatine metabolisms in the pathogenesis. Using metabolomic profiling in the whole blood and plasma of a mouse model of the disease, the Xia group progressively deciphered a central pathogenic mechanism, found in humans, promoting the polymerization of the hemoglobin
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