Journal
BRITISH JOURNAL OF PHARMACOLOGY
Volume 178, Issue 17, Pages 3463-3475Publisher
WILEY
DOI: 10.1111/bph.15492
Keywords
inflammation; kidney injury; olinciguat; sickle cell disease; soluble guanylate cyclase; vaso-occlusive crisis
Categories
Funding
- Deutsche Forschungsgemeinschaft [FOR 2060, FE 438/5-2, FE 438/6-2, 374031971 -TRR 240]
- National Institutes of Health [1F32HL142243, R01 HL069438]
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The sGC stimulator olinciguat attenuates inflammation, vaso-occlusion, and kidney injury in mouse models of SCD and systemic inflammation. Co-treatment with hydroxyurea enhances the anti-inflammatory effect of olinciguat, showing a potential beneficial impact on disease progression.
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 TNF alpha-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 TNF alpha-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 TNF alpha-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 TNF alpha-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-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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