Ferroportin Inhibition Attenuates Pulmonary Hypertension in Hypoxic Sickle Cell Disease Mice

Sickle cell disease (SCD) is a genetic 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 mmHg) when housed under sub-chronic (3-months) exposure to a moderately decreased oxygen level, approximately 15%. This model accelerates red blood cell 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 HbS 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 favored the attenuation of cardiopulmonary dysfunction. Indeed, attenuation of red cell sickling, less extra- 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.