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

Boris Tchernychev, Huihui Li, Sung Kyun Lee, Xin Gao, Raghunath Ramanarasimhaiah, Guang Liu, Katherine C. Hall, Sylvie G. Bernier, Juli E. Jones, Susanne Feil, Robert Feil, Emmanuel S. Buys, Regina M. Graul, Paul S. Frenette, Jaime L. Masferrer

Research output: Contribution to journalArticlepeer-review

Abstract

Background and Purpose: Reduced bioavailability of NO, a hallmark of sickle cell disease (SCD), contributes to intravascular inflammation, vasoconstriction, vaso-occlusion and organ damage observed in SCD patients. Soluble guanylyl cyclase (sGC) catalyses synthesis of cGMP in response to NO. cGMP-amplifying agents, including NO donors and phosphodiesterase 9 inhibitors, alleviate TNFα-induced inflammation in wild-type C57BL/6 mice and in ‘humanised’ mouse models of SCD. Experimental Approach: 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 agent, further augmented the anti-inflammatory effect of olinciguat. In the Berkeley mouse model of TNFα-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-h urine excretion, plasma levels of cystatin C and urinary excretion of N-acetyl-β-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.

Original languageEnglish (US)
Pages (from-to)3463-3475
Number of pages13
JournalBritish Journal of Pharmacology
Volume178
Issue number17
DOIs
StatePublished - Sep 2021

Keywords

  • inflammation
  • kidney injury
  • olinciguat
  • sickle cell disease
  • soluble guanylate cyclase
  • vaso-occlusive crisis

ASJC Scopus subject areas

  • Pharmacology

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