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

Robert P. Hebbel, Gregory M. Vercellotti

Research output: Contribution to journalReview articlepeer-review

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.

Original languageEnglish (US)
Pages (from-to)1505-1517
Number of pages13
JournalAmerican Journal of Hematology
Volume96
Issue number11
Early online dateJul 31 2021
DOIs
StatePublished - Nov 1 2021
Externally publishedYes

Bibliographical note

Funding Information:
Robert P. Hebbel serves on the S.A.B. of Emmaus Life Sciences; Gregory M. Vercellotti receives research funding from Behring and Astellas/Mitobridge.

Funding Information:
National Heart Lung and Blood Institute (R01HL114567).

Publisher Copyright:
© 2021 The Authors. American Journal of Hematology published by Wiley Periodicals LLC.

PubMed: MeSH publication types

  • Journal Article
  • Research Support, N.I.H., Extramural
  • Review

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