Ferroportin inhibition attenuates pulmonary hypertension in hypoxic sickle cell disease mice.

Abstract

Sickle cell disease (SCD) is a genetically inherited hemoglobinopathy arising from homozygosity or compound heterozygosity for a single base pair mutation in hemoglobin β-globin gene (HBB), and the severity is affected by allelic combinations, haplotypes, and gene products. Numerous SCD mouse models exist to study mechanism and therapeutic intervention, and each display some phenotypic features of human disease. Berkeley SCD mice demonstrate clinically relevant pulmonary hypertension (mean pulmonary artery pressure, 25-35 mm Hg) when housed under subchronic (3-month) exposure to a moderately decreased oxygen level, ∼15%. This model accelerates red blood cell (RBC) sickling and hemolysis, which perpetuates precapillary pulmonary vascular disease and right ventricular dysfunction. Iron restriction in SCD is reported to attenuate the frequency and severity of vaso-occlusive crisis through reducing sickle hemoglobin in RBCs. Vamifeport is an oral clinical stage ferroportin inhibitor shown to improve microcirculatory blood flow in Townes-SS mice. We hypothesized that vamifeport treatment may attenuate right ventricular dysfunction and pulmonary vascular remodeling in Berkeley SCD mice that express a pulmonary hypertension phenotype. Further, we hypothesized that lung and right ventricle metabolism and protein expressions would show an antioxidant and iron-regulatory response that favors the attenuation of cardiopulmonary dysfunction. Indeed, attenuation of red cell sickling, reduced extravascular and intravascular hemolysis, and normalization of cardiopulmonary dysfunction was observed after vamifeport treatment. We suggest that induction of mild iron-deficiency anemia may attenuate deadly sequelae of SCD, including cardiopulmonary dysfunction.