Differential effects of adenylyl cyclase-protein kinase A cascade on shear-induced changes of sickle cell deformability.
Protein kinase a
adenylyl cyclase
phosphodiesterase
red blood cell deformability
sickle cell disease
Journal
Clinical hemorheology and microcirculation
ISSN: 1875-8622
Titre abrégé: Clin Hemorheol Microcirc
Pays: Netherlands
ID NLM: 9709206
Informations de publication
Date de publication:
2019
2019
Historique:
pubmed:
16
7
2019
medline:
31
3
2020
entrez:
16
7
2019
Statut:
ppublish
Résumé
Erythrocyte deformability is impaired in sickle cell disease (SCD). The regulation of cytoskeletal protein organization plays a key role in erythrocyte deformability. The activation of adenylyl cyclase (AC)/cAMP/Protein kinase A (PKA) signaling pathway was associated with increased deformability in healthy erythrocytes, however the role of this pathway in SCD is unknown. We evaluated mechanical responses of sickle red blood cells under physiological levels of shear stress and the possible link between their deformability and AC/cAMP/PKA signaling pathway. The shearing of sickle red blood cells at physiological level (5 Pa) and the measurement of deformability were performed by a laser assisted optical rotational cell analyzer (LORRCA). Red blood cell deformability increased of 2.5-6.5% by blocking the activity of phosphodiesterase with Pentoxifylline (10μM) (p < 0.05). The inhibition of AC with SQ22536 (100μM) produced more significant rise in deformability (+4.8-12%, p < 0.01). No significant change was observed by the inhibition of PKA with H89 (10μM). Pentoxifylline and SQ22536 increased the deformability of sickle red blood cells under fluid shear stress. Modulation of the AC/cAMP/PKA pathway could have the potential to be an effective therapeutic approach for SCD through shear-induced improvements of RBC deformability.
Sections du résumé
BACKGROUND
BACKGROUND
Erythrocyte deformability is impaired in sickle cell disease (SCD). The regulation of cytoskeletal protein organization plays a key role in erythrocyte deformability. The activation of adenylyl cyclase (AC)/cAMP/Protein kinase A (PKA) signaling pathway was associated with increased deformability in healthy erythrocytes, however the role of this pathway in SCD is unknown.
OBJECTIVE
OBJECTIVE
We evaluated mechanical responses of sickle red blood cells under physiological levels of shear stress and the possible link between their deformability and AC/cAMP/PKA signaling pathway.
METHODS
METHODS
The shearing of sickle red blood cells at physiological level (5 Pa) and the measurement of deformability were performed by a laser assisted optical rotational cell analyzer (LORRCA).
RESULTS
RESULTS
Red blood cell deformability increased of 2.5-6.5% by blocking the activity of phosphodiesterase with Pentoxifylline (10μM) (p < 0.05). The inhibition of AC with SQ22536 (100μM) produced more significant rise in deformability (+4.8-12%, p < 0.01). No significant change was observed by the inhibition of PKA with H89 (10μM).
CONCLUSION
CONCLUSIONS
Pentoxifylline and SQ22536 increased the deformability of sickle red blood cells under fluid shear stress. Modulation of the AC/cAMP/PKA pathway could have the potential to be an effective therapeutic approach for SCD through shear-induced improvements of RBC deformability.
Identifiants
pubmed: 31306111
pii: CH190563
doi: 10.3233/CH-190563
doi:
Substances chimiques
Cyclic AMP-Dependent Protein Kinases
EC 2.7.11.11
Adenylyl Cyclases
EC 4.6.1.1
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM