Bosentan attenuates sickle cell disease erythrocyte HbS polymerization and impaired deformability induced by endothelin-1

Can J Physiol Pharmacol. 2023 Dec 1;101(12):642-651. doi: 10.1139/cjpp-2022-0012. Epub 2023 Feb 23.

Abstract

The effects of endothelin-1 (ET-1) on erythrocytes from sickle cell disease (SCD) patients have been described, but mechanisms of ET-1 regarding primary erythrocyte functions remain unknown. ET-1 is a vasoconstrictor peptide produced by endothelial cells, and the expression of ET-1 is increased in SCD. The present study used ex vivo experiments with sickle cell erythrocytes, ET-1, and bosentan, a dual antagonist of ETA and ETB receptors. We performed a hemoglobin S (HbS) polymerization assay with three concentrations of ET-1 (1, 20, and 50 pg/mL) and bosentan (100 nmol/L). ET-1 increased HbS polymerization at all concentrations, and this effect was suppressed by bosentan. For the deformability assay, red blood cells (RBCs) were incubated on a Sephacryl column with the same concentrations of ET-1 and bosentan. ET-1 decreased deformability, and this effect was reversed by bosentan. To observe erythrocyte adhesion, ET-1 and bosentan were incubated with RBCs in thrombospondin-coated 96-well plate, which demonstrated that ET-1 decreased adhesion but that bosentan enhanced adhesion. We also assessed erythrocyte apoptosis and observed decreased eryptosis induced by ET-1, and these effects were inhibited bosentan. Thus, these findings demonstrated that ET-1 modulates HbS polymerization, erythrocyte deformability, adhesion to thrombospondin, and eryptosis, and these effects were suppressed or enhanced by bosentan.

Keywords: bosentan; endothelin-1; erythrocyte; sickle cell disease.

MeSH terms

  • Anemia, Sickle Cell* / drug therapy
  • Bosentan / pharmacology
  • Endothelial Cells / metabolism
  • Endothelin Receptor Antagonists / pharmacology
  • Endothelin-1* / metabolism
  • Endothelins
  • Erythrocyte Deformability
  • Erythrocytes / metabolism
  • Humans
  • Polymerization
  • Receptors, Endothelin / metabolism
  • Sulfonamides / pharmacology
  • Thrombospondins

Substances

  • Bosentan
  • Endothelin-1
  • Sulfonamides
  • Thrombospondins
  • Endothelin Receptor Antagonists
  • Receptors, Endothelin
  • Endothelins