Blockade of Endothelin-1 Receptor B Regulates Molecules of the Major Histocompatibility Complex in Sickle Cell Disease

Published: 15 December 2022| Version 1 | DOI: 10.17632/cmghb83rmm.1
Yaritza Inostroza-Nieves


Molecules of the Major Histocompatibility Complex (MHC) have been proposed in the pathophysiology of immune and vascular alterations leading to vaso-occlusive crises in Sickle Cell Disease (SCD). Endothelial cells express MHC molecules following exposure to cytokines. SCD is characterized, in part, by vascular endothelial cell activation, increased oxidative stress, sickle cell adhesion, and excess levels of the potent mitogen, endothelin-1 (ET-1). ET-1 activates endothelial cells, induces oxidative stress and inflammation in the vascular wall, and regulates erythrocyte homeostasis. However, the role of ET-1 on MHC regulation in SCD is unclear. We first studied two sickle transgenic knockout mouse models of moderate to severe disease phenotype, βSAntilles and Berkeley (BERK) mice, respectively. We observed significant increases in MHC molecule, H2-Aa mRNA levels in spleens, lungs and kidneys from transgenic sickle mice when compared to transgenic knockout mice expressing human hemoglobin A (HbA). Mice treated for 14 days with ET-1 receptor antagonists had a significant reduction in H2-Aa mRNA. Then we characterized the effect of ET-1 on MHC class II expression in the human endothelial cell line EA.hy926. We observed dose-dependent increases in the expression of MHC class II (HLA-DR) and MHC transcription factor (CIITA) that were significantly blocked by pre-incubation of cells with BQ788, a selective blocker of ET-1 type B receptors. Chromatin immunoprecipitation (ChIP) studies in EA.hy926 cells showed that ET-1 increased Histone H3 acetylation of the promoter region within; an event that was likewise blocked by BQ788. These results implicate ET-1 as a novel regulator of MHC class II molecules and suggest that ET-1 receptor blockade represents a promising therapeutic approach to regulate both immune and vascular responses in SCD.



San Juan Bautista School of Medicine


Endothelin, Sickle Cell Disease, Major Histocompatibility Complex