Multiple inducers of endothelial NOS (eNOS) dysfunction in sickle cell disease

Abstract

A characteristic aspect of the robust, systemic inflammatory state in sickle cell disease is dysfunction of endothelial nitric oxide synthase (eNOS). We identify 10 aberrant endothelial cell inputs, present in the specific sickle context, that are known to have the ability to cause eNOS dysfunction. These are: endothelial arginase depletion, asymmetric dimethylarginine, complement activation, endothelial glycocalyx degradation, free fatty acids, inflammatory mediators, microparticles, oxidized low density lipoproteins, reactive oxygen species, and Toll‐like receptor 4 signaling ligands. The effect of true eNOS dysfunction on clinical testing using flow‐mediated dilation can be simulated by two known examples of endothelial dysfunction mimicry (hemoglobin consumption of NO; and oxidation of smooth muscle cell soluble guanylate cyclase). This lends ambiguity to interpretation of such clinical testing. The presence of these multiple perturbing factors argues that a therapeutic approach targeting only a single injurious endothelial input (or either example of mimicry) would not be sufficiently efficacious. This would seem to argue for identifying therapeutics that directly protect eNOS function or application of multiple therapeutic approaches.

Assessment of Reticulocyte and Erythrocyte Parameters From Automated Blood Counts in Vaso-Occlusive Crisis on Sickle Cell Disease

“…An important disease mechanism involves the release of hemoglobin into the circulation during intravascular haemolysis ( 14 ). The release of hemoglobin into the plasma during haemolysis potently inhibits endothelial nitric oxide signaling, leading to endothelial cell dysfunction and nitric oxide resistance ( 16 ). Studies have shown correlations between the rate of haemolysis and levels of platelet activation and procoagulant factors in the blood ( 17 ).…”

Multi-Organ Morphological Findings in a Humanized Murine Model of Sickle Cell Trait

“…Our primary outcome is that the heterozygous mice; even in the absence of patent hematological differences compared to the controls; carry characteristic lesions of the tunica intima of small vessels, that are especially found in the liver, spleen, kidneys, and lungs. While anomalies of the endothelial lining associated with SCD-affected patients and mouse models have been previously reported [ 32 , 33 , 34 ], the evidence of their association with the SCT carrier condition is still fragmentary [ 35 , 36 ]. The histopathological differences among the SCD-affected, the SCT carrier, and control mice have been addressed in very few studies.…”

Pharmacogenomics of Drugs Used in β-Thalassemia and Sickle-Cell Disease: From Basic Research to Clinical Applications

“…For example, rs2070744 was found in the promoter region and rs1799983 within exon 7 (894 G>T, Glu-298Asp) and the frequency of these polymorphisms was particularly high in patients with severe SCD, associated with lower levels of plasma NO [199]. NO inducers should be considered as therapeutic tools in SCD [200,201]. Interestingly, evidence for the in vivo conversion of hydroxyurea to nitric oxide has been provided [202].…”