A preliminary study of phosphodiesterases and adenylyl cyclase signaling pathway on red blood cell deformability of sickle cell patients

Frontiers in Physiology

Physiology

Alexandra Gauthier¹  Ingrid Muniansi²  Celine Renoux²  Philippe Joly²  Camille Boisson²  Philippe Connes²  Elie Nader²  Ozlem Yalcin³  Elif Ugurel³  Evrim Goksel⁴ 

[1] Institut Hématologique et Oncologique Pédiatrique (IHOPe), Lyon, France;Laboratoire Interuniversitaire de Biologie de la Motricité (LIBM) EA7424, Team “Vascular Biology and Red Blood Cell”, Université Claude Bernard Lyon 1, Lyon, France;Laboratoire d’Excellence du Globule Rouge (Labex GR-Ex), PRES Sorbonne, Paris, France;Research Center for Translational Medicine (KUTTAM), Koc University, Istanbul, Türkiye;Department of Physiology, School of Medicine, Koc University, Istanbul, Türkiye;Research Center for Translational Medicine (KUTTAM), Koc University, Istanbul, Türkiye;Department of Physiology, School of Medicine, Koc University, Istanbul, Türkiye;Graduate School of Health Sciences, Koc University, Istanbul, Türkiye;

关键词: sickle cell disease;    deformability;    shear stress;    adenylyl cyclase;    phosphodiesterases;    protein kinase A;   

DOI  :  10.3389/fphys.2023.1215835

 received in 2023-05-02, accepted in 2023-09-01,  发布年份 2023

来源: Frontiers

【 摘 要 】

Sickle cell disease (SCD) is an inherited hemoglobinopathy characterized by chronic anemia, intravascular hemolysis, and the occurrence of vaso-occlusive crises due to the mechanical obstruction of the microcirculation by poorly deformable red blood cells (RBCs). RBC deformability is a key factor in the pathogenesis of SCD, and is affected by various factors. In this study, we investigated the effects of adenylyl cyclase (AC) signaling pathway modulation and different phosphodiesterase (PDE) modulatory molecules on the deformability and mechanical stress responses of RBC from SCD patients (HbSS genotype) by applying 5 Pa shear stress with an ektacytometer (LORRCA). We evaluated RBC deformability before and after the application of shear stress. AC stimulation with Forskolin had distinct effects on RBC deformability depending on the application of 5 Pa shear stress. RBC deformability was increased by Forskolin before shear stress application but decreased after 5 Pa shear stress. AC inhibition with SQ22536 and protein kinase A (PKA) inhibition with H89 increased RBC deformability before and after the shear stress application. Non-selective PDE inhibition with Pentoxifylline increased RBC deformability. However, modulation of the different PDE types had distinct effects on RBC deformability, with PDE1 inhibition by Vinpocetine increasing deformability while PDE4 inhibition by Rolipram decreased RBC deformability after the shear stress application. The effects of the drugs varied greatly between patients suggesting some could benefit from one drug while others not. Developing drugs targeting the AC signaling pathway could have clinical applications for SCD, but more researches with larger patient cohorts are needed to identify the differences in the responses of sickle RBCs.

【 授权许可】

Unknown   
Copyright © 2023 Goksel, Ugurel, Nader, Boisson, Muniansi, Joly, Renoux, Gauthier, Connes and Yalcin.