title: Intestine-specific Disruption of Hypoxia-inducible Factor (HIF)-2α Improves Anemia in Sickle Cell Disease.
abstract: Sickle cell disease (SCD) is caused by genetic defects in the β-globin chain. SCD is a frequently inherited blood disorder, and sickle cell anemia is a common type of hemoglobinopathy. During anemia, the hypoxic response via the transcription factor hypoxia-inducible factor (HIF)-2α is highly activated in the intestine and is essential in iron absorption. Intestinal disruption of HIF-2α protects against tissue iron accumulation in iron overload anemias. However, the role of intestinal HIF-2α in regulating anemia in SCD is currently not known. Here we show that in mouse models of SCD, disruption of intestinal HIF-2α significantly decreased tissue iron accumulation. This was attributed to a decrease in intestinal iron absorptive genes, which were highly induced in a mouse model of SCD. Interestingly, disruption of intestinal HIF-2α led to a robust improvement in anemia with an increase in RBC, hemoglobin, and hematocrit. This was attributed to improvement in RBC survival, hemolysis, and insufficient erythropoiesis, which is evident from a significant decrease in serum bilirubin, reticulocyte counts, and serum erythropoietin following intestinal HIF-2α disruption. These data suggest that targeting intestinal HIF-2α has a significant therapeutic potential in SCD pathophysiology.
authors: From the Department of Molecular and Integrative Physiology.
authors: Nupur
authors: N
authors: Das
authors: From the Department of Molecular and Integrative Physiology.
authors: Liwei
authors: L
authors: Xie
authors: From the Department of Molecular and Integrative Physiology.
authors: Sadeesh K
authors: SK
authors: Ramakrishnan
authors: Department of Pediatrics, and.
authors: Andrew
authors: A
authors: Campbell
authors: the Abramson Research Center, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania 19104.
authors: Stefano
authors: S
authors: Rivella
authors: From the Department of Molecular and Integrative Physiology, Department of Internal Medicine, Division of Gastroenterology, University of Michigan Medical School, Ann Arbor, Michigan 48109 and shahy@umich.edu.
authors: Yatrik M
authors: YM
authors: Shah
mesh_terms: D000755:Anemia, Sickle Cell / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology*; D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D007413:Intestinal Mucosa / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D000099162:Endothelial PAS Domain-Containing Protein 1
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D000099162:Endothelial PAS Domain-Containing Protein 1
keywords: HIF-2α; anemia; hypoxia; hypoxia-inducible factor (HIF); intestinal epithelium; iron; iron homeostasis; iron metabolism; sickle cell disease