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

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.

• Authors: 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
• Journal: British journal of pharmacology (Br J Pharmacol) Vol. 178 Issue 17 Pg. 3463-3475 (09 2021) ISSN: 1476-5381 [Electronic] England
• PMID: 33864386 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: © 2021 Cyclerion Therapeutics Inc. British Journal of Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.

Chemical References

• Soluble Guanylyl Cyclase

Topics

• Anemia, Sickle Cell (complications, drug therapy)
• Animals
• Humans
• Inflammation
• Mice
• Mice, Inbred C57BL
• Soluble Guanylyl Cyclase
• Vascular Diseases