Differential effects of adenylyl cyclase-protein kinase A cascade on shear-induced changes of sickle cell deformability

Article type: Research Article

Authors: Ugurel, Elif^a | Connes, Philippe^{b; c; d} | Yavas, Gokce^{a; 1} | Eglenen, Buse^{a; 1} | Turkay, Mine^{a; 1} | Aksu, Ali Cenk^a | Renoux, Celine^{b; c; e} | Joly, Philippe^{b; c; e} | Gauthier, Alexandra^{b; c; f} | Hot, Arnaud^g | Bertrand, Yves^f | Cannas, Giovanna^{b; c; g} | Yalcin, Ozlem^{a; *}

Affiliations: [a] Department of Physiology, Koç University School of Medicine, Sariyer, Istanbul, Turkey | [b] Laboratoire Interuniversitaire de Biologie de la Motricité (LIBM) EA7424, Team « Vascular Biology and Red Blood Cell », Université Claude Bernard Lyon 1, Lyon, France | [c] Laboratoire d’Excellence du Globule Rouge (Labex GR-Ex), PRES Sorbonne, Paris, France | [d] Institut Universitaire de France (IUF), Paris, France | [e] UF de biochimie des pathologies érythrocytaires, Centre de Biologie Est, Hospices Civils de Lyon, Lyon, France | [f] Institut d’hématologie et d’oncologie pédiatrique (IHOP), Hospices Civils de Lyon, Lyon, France | [g] Clinique de Médecine Ambulatoire/Hématologie Hôpital Edouard Herriot, Lyon, Lyon, France

Correspondence: [*] Corresponding author: Dr. Ozlem Yalcin, Koc University School of Medicine, Sariyer, Istanbul, Turkey. Tel.: +90 212 338 1136; Fax: +90 212 338 1168; E-mail: ozlemyalcin@ku.edu.tr.

Note: [1] These authors contributed equally to this work.

Abstract: 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: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: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: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: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.

Keywords: Protein kinase a, adenylyl cyclase, phosphodiesterase, red blood cell deformability, sickle cell disease

DOI: 10.3233/CH-190563

Journal: Clinical Hemorheology and Microcirculation, vol. 73, no. 4, pp. 531-543, 2019