Multiple inducers of endothelial NOS (eNOS) dysfunction in sickle cell disease.
Robert P HebbelGregory M VercellottiPublished in: American journal of hematology (2021)
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.
Keyphrases
- nitric oxide synthase
- endothelial cells
- sickle cell disease
- nitric oxide
- toll like receptor
- oxidative stress
- smooth muscle
- high glucose
- reactive oxygen species
- vascular endothelial growth factor
- hydrogen peroxide
- fatty acid
- inflammatory response
- small molecule
- stem cells
- pi k akt
- cell therapy
- single cell
- signaling pathway
- cancer therapy
- drug delivery
- cell proliferation