Inhibition of heme oxygenase ameliorates anemia and reduces iron overload in a β-thalassemia mouse model

Abstract

Thalassemias are a heterogeneous group of red blood cell disorders, considered a major cause of morbidity and mortality among genetic diseases. However, there is still no universally available cure for thalassemias. The underlying basis of thalassemia pathology is the premature apoptotic destruction of erythroblasts causing ineffective erythropoiesis. In β-thalassemia, β-globin synthesis is reduced causing α-globin accumulation. Unpaired globin chains, with heme attached to them, accumulate in thalassemic erythroblasts causing oxidative stress and the premature cell death. We hypothesize that in β-thalassemia heme oxygenase (HO) 1 could play a pathogenic role in the development of anemia and ineffective erythropoiesis. To test this hypothesis, we exploited a mouse model of β-thalassemia intermedia, Th3/ We observed that HO inhibition using tin protoporphyrin IX (SnPP) decreased heme-iron recycling in the liver and ameliorated anemia in the Th3/ mice. SnPP administration led to a decrease in erythropoietin and increase in hepcidin serum levels, changes that were accompanied by an alleviation of ineffective erythropoiesis in Th3/ mice. Additionally, the bone marrow from Th3/ mice treated with SnPP exhibited decreased heme catabolism and diminished iron release as well as reduced apoptosis. Our results indicate that the iron released from heme because of HO activity contributes to the pathophysiology of thalassemia. Therefore, new therapies that suppress heme catabolism may be beneficial in ameliorating the anemia and ineffective erythropoiesis in thalassemias.

Distinct Iron Deposition Profiles of Liver Zones in Various Models with Iron Homeostasis Disorders

“…As shown in Figure S3 in the Supporting Information, a higher level in L1‐2 and L1‐3 and a lower level in L4‐3 for the tissue MDA were found, respectively, in agreement with their differential tissue iron content. In support of this finding, discrepant induction of crucial regulators against oxidative stress, including nuclear factor (erythroid‐derived2)‐like2 (Nrf2)37 and heme oxygenase‐1 (HO‐1),38 was demonstrated in these zones (Figure 1F and Figure S2D,E, Supporting Information), consistent with their corresponding iron levels.…”

Oral ferroportin inhibitor ameliorates ineffective erythropoiesis in a model of β-thalassemia

“…Upon maturation, RBCs from WT mice progressively eliminated their mitochondria, with only 1.5% of terminally differentiated RBCs retaining RBCs for phagocytosis by scavenging macrophages that deliver the damaged RBCs to spleen and liver for degradation (33). The released heme is catabolized by heme oxygenase 1 (HMOX1), which is upregulated in β-thalassemia due to excessive RBC apoptosis (34). VIT-2763 treatment significantly reduced the expression of Hmox1 in livers of Hbb th3/+ mice, most likely as a result of the decreased RBC turnover ( Figure 10B).…”

Bitopertin, a selective oral GLYT1 inhibitor, improves anemia in a mouse model of β-thalassemia

“…Heme plays a key role in normal erythropoiesis and in the alterations observed in β-thal erythropoiesis (3,5,17). We and others have shown biphasic behavior in heme biosynthesis, characterized by heme accumulation in the early phase of β-thal erythropoiesis, followed by a relative heme reduction in the late phase of β-thal erythropoiesis (3).…”

“…Previous studies have shown that modulation of heme homeostasis might affect erythropoiesis (16) and beneficially affect β-thal erythroid maturation (17). In erythroblasts, glycine uptake via the glycine carrier system, GlyT1, is a key determinant of the rate of heme biosynthesis and bioavailability (18,19).…”