THE SOLUBLE GUANYLATE CYCLASE STIMULATOR OLINCIGUAT ATTENUATES LEUKOCYTE/ENDOTHELIAL CELL INTERACTIONS IN BERKELEY SCD MICE
Author(s): ,
Huihui Li
Affiliations:
Cell Biology,Albert Einstein College of Medicine,Bronx,United States
,
Sung-Kyun Lee
Affiliations:
Cell Biology,Albert Einstein College of Medicine,Bronx,United States
,
Boris Tchernychev
Affiliations:
Cyclerion Therapeutics, Inc.,Cambridge,United States
,
Regina. M. Graul
Affiliations:
Cyclerion Therapeutics, Inc.,Cambridge,United States
,
Jaime Masferrer
Affiliations:
Cyclerion Therapeutics, Inc.,Cambridge,United States
Paul Frenette
Affiliations:
Cell Biology,Albert Einstein College of Medicine,Bronx,United States
EHA Library. Li H. Jun 15, 2019; 267138; PS1521
Huihui Li
Huihui Li
Contributions
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Abstract

Abstract: PS1521

Type: Poster Presentation

Presentation during EHA24: On Saturday, June 15, 2019 from 17:30 - 19:00

Location: Poster area

Background
Patients with hemolytic anemias such as sickle cell disease (SCD) have reduced nitric oxide (NO) bioavailability (1).  NO insufficiency results in suppression of NO-cyclic guanosine monophosphate (cGMP)-protein kinase G (PKG) signaling pathway and has been implicated in vasoconstriction, intravascular inflammation, and formation of heterocellular vaso-occlusive aggregates in the venous microcirculation of SCD patients.  In mouse models of SCD, cGMP amplifying agents, including NO donors and inhibitors of phosphodiesterase 9 (PDE9), reduce heterotypic adhesive interactions mediated by sickled red blood cells, leukocytes, platelets and activated endothelial cells (2, 3).  Co-treatment of PDE9 inhibitors with hydroxyurea (HU) augments anti-inflammatory and anti-adhesive effects in these models (2, 3).

Aims
In response to NO binding, soluble guanylate cyclase (sGC) catalyzes synthesis of cGMP from GTP.  Therefore, we evaluated the effect of the sGC stimulator olinciguat on leukocyte-endothelial cell interactions in a mouse model of vaso-occlusive crisis (VOC).

Methods
The effect of olinciguat in the absence or presence of HU on leukocyte-endothelial cell interactions was studied in chimeric C57BL/6 mice engrafted with the bone marrow from Berkeley SCD mice.  Vaso-occlusive crisis in sickle cell mice was induced by intraperitoneal injection of mouse TNFα (0.5 μg/mouse).  Olinciguat (10 mg/kg) and HU (100 mg/kg) were administered by oral gavage, 30 minutes before treatment with TNFα.  Leukocyte-endothelial cell interactions in postcapillary venules of mouse cremaster muscle were analyzed by intravital microscopy 90 minutes after TNFα challenge. A flow rate and centerline blood shear rate in each venule was measured using optical Doppler velocimeter.

Results
Animals pretreated with TNFα had significantly higher adhesion efficiency of leukocytes to the vascular wall compared to non-treated, naïve animals (mean±SEM; 3.5±0.8 and 0.7±0.1 cells/100 μm2/rolling flux, respectively; p<0.001).  Adhesion efficiency of leukocytes was lower in mice pretreated with either olinciguat (10 mg/kg) or HU (100 mg/kg) than in vehicle-treated mice (0.9±0.1, 1.6±0.4 and 3.5±0.8 cells/100 μm2/rolling flux, respectively; p<0.001).  Adhesion efficiency of leukocytes to activated endothelium was lowest in mice treated with both olinciguat and HU (0.5±0.1 cells/100 μm2/rolling flux).  Blood flow in TNFα-challenged mice that were pretreated with olinciguat, HU, or their combination was greater than vehicle-treated controls (287±22, 277±29, 261±14, and 178±15 pL/s respectively, p≤0.01).  Relative to vehicle-treated mice, blood shear rates were only enhanced in HU and combination treated animals (497±43 s-1, 808±82, and 722±30 respectively, p≤0.01).  Finally, only mice treated with both olinciguat and HU survived longer (hours) than mice in the vehicle group (3.4±0.3 vs 2.8±0.3, p=0.05).

Conclusion
In summary, the data indicate that in a TNFα-induced model of VOC, pretreatment with the sGC stimulator olinciguat improved blood flow and attenuated leukocyte endothelial cell interactions in the venous microcirculation of sickle cell mice.

 

References

1. Kato GJ., et al., J.Clin.Invest. 2017; 127(3):750

2. Almeida CB., et al., Blood 2012 120(14):2879

3. Jasuja R., et al., Blood 2014 124(21):2694

Session topic: 26. Sickle cell disease

Keyword(s): Sickle cell disease

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