Beneficial Effects of Soluble Guanylyl Cyclase Stimulation and Activation in Sickle Cell Disease Are Amplified by Hydroxyurea: In Vitro and In Vivo Studies

Ferreira, Wilson A.; Chweih, Hanan; Lanaro, Carolina; Almeida, Camila B.; Brito, Pâmela L.; Gotardo, Érica M.F.; Torres, Lidiane de Souza; Miguel, Lediana I.; Franco‐Penteado, Carla F.; Leonardo, Flávia C.; Garcia, Flávia; Saad, Sara T Olalla; Frenette, Paul S.; Brockschnieder, Damian; Costa, Fernando Ferreira; Stasch, Johannes‐Peter; Sandner, Peter; Conran, Nicola

doi:10.1124/jpet.119.264606

Cited by 13 publications

(14 citation statements)

References 57 publications

(84 reference statements)

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“…The effect of olinciguat on plasma levels of sE‐selectin was augmented by co‐administration of hydroxyurea. Similarly, co‐administration of hydroxyurea was recently reported to potentiate the beneficial effects of other sGC agonists in a TNFα‐induced mouse model of vaso‐occlusion (Ferreira et al, 2020 ).…”

Section: Discussionmentioning

confidence: 89%

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Olinciguat, a stimulator of soluble guanylyl cyclase, attenuates inflammation, vaso‐occlusion and nephropathy in mouse models of sickle cell disease

Tchernychev

Lee

et al. 2021

British J Pharmacology

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Background and Purpose: Reduced nitric oxide (NO) bioavailability, a hallmark of sickle cell disease (SCD), contributes to intravascular inflammation, vasoconstriction, vasoocclusion, and organ damage observed in SCD patients. Soluble guanylyl cyclase (sGC) catalyzes synthesis of cyclic guanosine monophosphate (cGMP) in response to NO. cGMP amplifying agents, including NO donors and phosphodiesterase 9 inhibitors, alleviate tumor necrosis factor alpha (TNFα)-induced inflammation in wild-type C57BL/6 mice and in "humanized" mouse models of SCD. Experimental Approach: The effects of the sGC stimulator olinciguat on intravascular inflammation and renal injury were studied in acute (C57BL6 and Berkeley mice) and chronic (Townes mice) mouse models of TNFα-induced and systemic inflammation associated with SCD. Key Results: Acute treatment with olinciguat attenuated increases in plasma biomarkers of endothelial cell activation and leukocyte endothelial cell interactions in TNFα-challenged mice. Co-treatment with hydroxyurea, an FDA-approved SCD therapeutic, further augmented the anti-inflammatory effect of olinciguat. In the Berkeley mouse model of TNFa-induced vaso-occlusive crisis, a single dose of olinciguat attenuated leukocyte/endothelial cell interactions, improved blood flow, and prolonged survival time compared to vehicle-treated mice. In Townes SCD mice, plasma biomarkers of inflammation and endothelial cell activation were lower in olinciguat-than in vehicle-treated mice. In addition, kidney mass, water consumption, 24-hour urine excretion, plasma levels of cystatin C, and urinary excretion of N-acetyl-beta-d-glucosaminidase and neutrophil gelatinase-associated lipocalin were lower in Townes mice treated with olinciguat than in vehicle-treated mice. Conclusion and Implications:Our results suggest that the sGC stimulator olinciguat attenuates inflammation, vaso-occlusion, and kidney injury in mouse models of SCD and systemic inflammation.

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Section: Discussionmentioning

confidence: 89%

“…(McArthur et al, 2020 ). Recently, the co‐administration of hydroxyurea was shown to potentiate the ability of an sGC stimulator or activator to decrease TNFα‐induced leukocyte recruitment in a mouse model of vaso‐occlusion (Ferreira et al, 2020 ).…”

Section: Introductionmentioning

confidence: 99%

Olinciguat, a stimulator of soluble guanylyl cyclase, attenuates inflammation, vaso‐occlusion and nephropathy in mouse models of sickle cell disease

Tchernychev

Lee

et al. 2021

British J Pharmacology

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“…38 Evidence from in vivo and in vitro studies point to hydroxyurea as a potent antiinflammatory drug that promotes a decrease in neutrophil counts, prevents neutrophil activation and adhesion, and improves endothelial function. 41,42 New drug therapies have been approved by the FDA within the last 5 years, including L-glutamine, 43 an amino acid with anti-oxidant properties; crizanlizumab, 44 a humanized antibody targeting P-selectin, which is expressed by platelets and endothelial cells; and voxelotor, 45 a modulator of hemoglobin-oxygen affinity. Besides targeting distinct pathways of SCD pathophysiology, they all directly or indirectly reduce leukocyte count, activation, and adhesion, further supporting the prominent inflammatory aspect of SCD and the fundamental role of leukocytes to disease pathophysiology.…”

Section: S I Ckle Cell D Is E a S E A S An Infl Ammatory Dis E A S Ementioning

confidence: 99%

Neutrophils as drivers of vascular injury in sickle cell disease

Torres

Hidalgo

2022

Immunological Reviews

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Summary While neutrophils are the main effectors of protective innate immune responses, they are also key players in inflammatory pathologies. Sickle cell disease (SCD) is a genetic blood disorder in which red blood cells (RBCs) are constantly destroyed in the circulation which generates a highly inflammatory environment that culminates in vascular occlusions. Vaso‐occlusion is the hallmark of SCD and a predictor of disease severity. Neutrophils initiate and propagate SCD‐related vaso‐occlusion through adhesive interactions with the activated and dysfunctional endothelium, sickle RBCs, and platelets, leading to acute and chronic complications that progress to irreversible organ damage and ultimately death. The use of SCD humanized mouse models, in combination with in vivo imaging techniques, has emerged as a fundamental tool to understand the dynamics of neutrophils under complex inflammatory contexts and their contribution to vascular injury in SCD. In this review, we discuss the various mechanisms by which circulating neutrophils sense and respond to the wide range of stimuli present in the blood of SCD patients and mice. We argue that the central role of neutrophils in SCD can be rationalized to develop targets for the management of clinical complications in SCD patients.

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“…Other sGC stimulators effectively inhibited leukocyte recruitment and the adhesive properties of neutrophils to fibronectin in sickle cell mice. These agents significantly reduced the frequency of vaso-occlusive episodes, complementing their established dose-dependent blood pressure-lowering effects [ 85 ]. Olinciguat, another sGC stimulator that is currently in phase II clinical development for use in patients with sickle cell anemia, not only reduces BP in humans and in hypertensive and normotensive rats but also successfully reduces inflammatory mechanisms in TNF-stimulated mice.…”

Section: Current Pharmacological Classes Of Antihypertensive Agentsmentioning

confidence: 99%

Current and Emerging Classes of Pharmacological Agents for the Management of Hypertension

Ojha

Ruddaraju

Sabapathy

et al. 2021

Am J Cardiovasc Drugs

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Cardiovascular disease accounts for more than 17 million deaths globally every year, of which complications of hypertension account for 9.4 million deaths worldwide. Early detection and management of hypertension can prevent costly interventions, including dialysis and cardiac surgery. Non-pharmacological approaches for managing hypertension commonly involve lifestyle modification, including exercise and dietary regulations such as reducing salt and fluid intake; however, a majority of patients will eventually require antihypertensive medications. In 2020, the International Society of Hypertension published worldwide guidelines in its efforts to reduce the global prevalence of raised blood pressure (BP) in adults aged 18 years or over. Currently, several classes of medications are used to control hypertension, either as mono- or combination therapy depending on the disease severity. These drug classes include those that target the renin-angiotensin-aldosterone system (RAAS) and adrenergic receptors, calcium channel blockers, diuretics and vasodilators. While some of these classes of medications have shown significant benefits in controlling BP and reducing cardiovascular mortality, the prevalence of hypertension remains high. Significant efforts have been made in developing new classes of drugs that lower BP; these medications exert their therapeutic benefits through different pathways and mechanism of actions. With several of these emerging classes in phase III clinical trials, it is hoped that the discovery of these novel therapeutic avenues will aid in reducing the global burden of hypertension.

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Beneficial Effects of Soluble Guanylyl Cyclase Stimulation and Activation in Sickle Cell Disease Are Amplified by Hydroxyurea: In Vitro and In Vivo Studies

Abstract: Soluble guanylyl cyclase stimulation in sickle cell disease.

Cited by 13 publications

References 57 publications

Olinciguat, a stimulator of soluble guanylyl cyclase, attenuates inflammation, vaso‐occlusion and nephropathy in mouse models of sickle cell disease

Olinciguat, a stimulator of soluble guanylyl cyclase, attenuates inflammation, vaso‐occlusion and nephropathy in mouse models of sickle cell disease

Neutrophils as drivers of vascular injury in sickle cell disease

Current and Emerging Classes of Pharmacological Agents for the Management of Hypertension

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