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Multiple organ pathology, metabolic abnormalities and impaired homeostasis of reactive oxygen species in Epas1−/− mice

Abstract

Hypoxia-inducible factor (HIF) transcription factors respond to multiple environmental stressors, including hypoxia and hypoglycemia. We report that mice lacking the HIF family member HIF-2α (encoded by Epas1) have a syndrome of multiple-organ pathology, biochemical abnormalities and altered gene expression patterns. Histological and ultrastructural analyses showed retinopathy, hepatic steatosis, cardiac hypertrophy, skeletal myopathy, hypocellular bone marrow, azoospermia and mitochondrial abnormalities in these mice. Serum and urine metabolite studies showed hypoglycemia, lactic acidosis, altered Krebs cycle function and dysregulated fatty acid oxidation. Biochemical assays showed enhanced generation of reactive oxygen species (ROS), whereas molecular analyses indicated reduced expression of genes encoding the primary antioxidant enzymes (AOEs). Transfection analyses showed that HIF-2α could efficiently transactivate the promoters of the primary AOEs. Prenatal or postnatal treatment of Epas1−/− mice with a superoxide dismutase (SOD) mimetic reversed several aspects of the null phenotype. We propose a rheostat role for HIF-2α that allows for the maintenance of ROS as well as mitochondrial homeostasis.

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Figure 1: Baseline and gross anatomical studies.
Figure 2: Histological studies of skeletal muscle, heart and liver.
Figure 3: Histological studies of eye, bone and testis.
Figure 4: Histochemical and electron microscopy mitochondrial studies.
Figure 5: Acyl-carnitine profiles.
Figure 6: Biochemical studies.
Figure 7: Molecular and transfection studies.
Figure 8: Rescue studies.

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Acknowledgements

We thank A. Das, L. Wang and V. Jones for technical assistance; the University of Texas Southwestern Medical Center Molecular Pathology Core group for histologic expertise; D. Bellotto and the University of Texas Southwestern Medical Center Imaging Core for guidance; R. Estabrook, R. Haller and G. Thomas for providing suggestions with mitochondrial assays; J. Repa for assistance with real-time RT-PCR; J. Herz and S. Hoffman for donating antibodies; D. Foster, R. S. Williams and S. McKnight for support; and A. Zinn, L. Terada and C. K. Garcia for critically reviewing this manuscript. J.A.G. is supported by funds from the National Institutes of Health, American Heart Association and Donald W. Reynolds Foundation.

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Correspondence to Joseph A Garcia.

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Scortegagna, M., Ding, K., Oktay, Y. et al. Multiple organ pathology, metabolic abnormalities and impaired homeostasis of reactive oxygen species in Epas1−/− mice. Nat Genet 35, 331–340 (2003). https://doi.org/10.1038/ng1266

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