Nitric Oxide–Independent Soluble Guanylate Cyclase Activation Improves Vascular Function and Cardiac Remodeling in Sickle Cell Disease

Abstract

Sickle cell disease (SCD) is associated with intravascular hemolysis and oxidative inhibition of nitric oxide (NO) signaling. BAY 54-6544 is a small-molecule activator of oxidized soluble guanylate cyclase (sGC), which, unlike endogenous NO and the sGC stimulator, BAY 41-8543, preferentially binds and activates heme-free, NO-insensitive sGC to restore enzymatic cGMP production. We tested orally delivered sGC activator, BAY 54-6544 (17 mg/kg/d), sGC stimulator, BAY 41-8543, sildenafil, and placebo for 4-12 weeks in the Berkeley transgenic mouse model of SCD (BERK-SCD) and their hemizygous (Hemi) littermate controls (BERK-Hemi). Right ventricular (RV) maximum systolic pressure (RVmaxSP) was measured using micro right-heart catheterization. RV hypertrophy (RVH) was determined using Fulton's index and RV corrected weight (ratio of RV to tibia). Pulmonary artery vasoreactivity was tested for endothelium-dependent and -independent vessel relaxation. Right-heart catheterization revealed higher RVmaxSP and RVH in BERK-SCD versus BERK-Hemi, which worsened with age. Treatment with the sGC activator more effectively lowered RVmaxSP and RVH, with 90-day treatment delivering superior results, when compared with other treatments and placebo groups. In myography experiments, acetylcholine-induced (endothelium-dependent) and sodium-nitroprusside-induced (endothelium-independent NO donor) relaxation of the pulmonary artery harvested from placebo-treated BERK-SCD was impaired relative to BERK-Hemi but improved after therapy with sGC activator. By contrast, no significant effect for sGC stimulator or sildenafil was observed in BERK-SCD. These findings suggest that sGC is oxidized in the pulmonary arteries of transgenic SCD mice, leading to blunted responses to NO, and that the sGC activator, BAY 54-6544, may represent a novel therapy for SCD-associated pulmonary arterial hypertension and cardiac remodeling.

Smooth muscle cytochrome b5 reductase 3 deficiency accelerates pulmonary hypertension development in sickle cell mice

“…Similar to other studies of PH in Townes or Berkeley SS mice, 38,43,44 Figure 4. Three weeks of SMC CYB5R3 knockdown has no effect on cardiopulmonary hemodynamics or cardiac morphology in AS chimeras.…”

“…Microcatheterization was performed as previously described. 38 Briefly, mice were anesthetized with etomidate/urethane (9/1.1 mg/kg intraperitoneally) and body temperature (37°C) maintained by heating pad. The right neck was incised, exposing the external jugular vein for catheterization (1.2 F micropressure-volume).…”

Soluble Guanylate Cyclase Stimulators and Activators

“…As noted above, the sGC stimulator BAY 41-2272 and NO reduced leukocyte rolling and adhesion in an eNOS deficient mouse model (Ahluwalia et al 2004), and the sGC stimulator olinciguat reduced makers of vascular inflammation and increased leukocyte rolling and velocity in a TNFα mouse model (Tchernychev et al 2017). Chronic oral administration of the sGC activator cinaciguat improved endothelial function and reversed pulmonary hypertension and cardiac remodeling in a mouse model of SCD without affecting systemic blood pressure (Potoka et al 2018). In a humanized SCD mouse model of TNFα-induced acute vaso-occlusion, BAY 73-6691, a PDE9 inhibitor, reduced leukocyte recruitment and red blood cell-leukocyte interactions, and improved leukocyte rolling and adhesion (Almeida et al 2012).…”

cGMP modulation therapeutics for sickle cell disease

“…143 With regard to the potential use of sGC activators in SCD, the chronic oral administration of the sGC activator, BAY 54-6544, was found to decrease cardiac remodeling in mice with SCD more efficiently than the sGC stimulator, BAY 41-8543, without altering systemic blood pressure. 102 Furthermore, the BAY 54-6544 sGC activator improved ex vivo endothelium-dependent and -independent relaxation of the pulmonary artery of SCD mice, while the sGC stimulator was unable to augment vasorelaxation. 102 Data suggest that sGC is oxidized in the pulmonary arteries of SCD mice, hindering NO-induced responses 144 ; sGC activation may therefore represent a potential therapy that bypasses the need for NO-induced responses to improve vasorelaxation in SCD and potentially provide therapy for pulmonary arterial hypertension and cardiac remodeling in these patients.…”

“…102 Furthermore, the BAY 54-6544 sGC activator improved ex vivo endothelium-dependent and -independent relaxation of the pulmonary artery of SCD mice, while the sGC stimulator was unable to augment vasorelaxation. 102 Data suggest that sGC is oxidized in the pulmonary arteries of SCD mice, hindering NO-induced responses 144 ; sGC activation may therefore represent a potential therapy that bypasses the need for NO-induced responses to improve vasorelaxation in SCD and potentially provide therapy for pulmonary arterial hypertension and cardiac remodeling in these patients. While clinical findings for cinaciguat were disappointing for treating acute decompensated heart failure, the compound did exert some clinical benefits, such as a rapid and sustained reduction in pulmonary capillary wedge pressure.…”