Assuntos
Corticosteroides/efeitos adversos , Pessoas com Deficiência , Articulação do Quadril/patologia , Osteonecrose/induzido quimicamente , Articulação do Ombro/patologia , Idoso , Diagnóstico Diferencial , Feminino , Necrose da Cabeça do Fêmur/induzido quimicamente , Articulação do Quadril/diagnóstico por imagem , Humanos , Doença Iatrogênica , Imageamento por Ressonância Magnética , Articulação do Ombro/diagnóstico por imagemRESUMO
Cell culture studies have implicated the oxygen-sensitive hypoxia-inducible factor (HIF) prolyl hydroxylase PHD3 in the regulation of neuronal apoptosis. To better understand this function in vivo, we have created PHD3(-/-) mice and analyzed the neuronal phenotype. Reduced apoptosis in superior cervical ganglion (SCG) neurons cultured from PHD3(-/-) mice is associated with an increase in the number of cells in the SCG, as well as in the adrenal medulla and carotid body. Genetic analysis by intercrossing PHD3(-/-) mice with HIF-1a(+/-) and HIF-2a(+/-) mice demonstrated an interaction with HIF-2alpha but not HIF-1alpha, supporting the nonredundant involvement of a PHD3-HIF-2alpha pathway in the regulation of sympathoadrenal development. Despite the increased number of cells, the sympathoadrenal system appeared hypofunctional in PHD3(-/-) mice, with reduced target tissue innervation, adrenal medullary secretory capacity, sympathoadrenal responses, and systemic blood pressure. These observations suggest that the role of PHD3 in sympathoadrenal development extends beyond simple control of cell survival and organ mass, with functional PHD3 being required for proper anatomical and physiological integrity of the system. Perturbation of this interface between developmental and adaptive signaling by hypoxic, metabolic, or other stresses could have important effects on key sympathoadrenal functions, such as blood pressure regulation.
Assuntos
Glândulas Suprarrenais/anormalidades , Hipotensão/etiologia , Pró-Colágeno-Prolina Dioxigenase/deficiência , Sistema Nervoso Simpático/anormalidades , Adaptação Fisiológica , Glândulas Suprarrenais/patologia , Glândulas Suprarrenais/fisiopatologia , Animais , Apoptose , Sequência de Bases , Fatores de Transcrição Hélice-Alça-Hélice Básicos/deficiência , Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Fatores de Transcrição Hélice-Alça-Hélice Básicos/fisiologia , Primers do DNA/genética , Feminino , Marcação de Genes , Hipotensão/genética , Hipotensão/patologia , Hipotensão/fisiopatologia , Subunidade alfa do Fator 1 Induzível por Hipóxia/deficiência , Subunidade alfa do Fator 1 Induzível por Hipóxia/genética , Subunidade alfa do Fator 1 Induzível por Hipóxia/fisiologia , Masculino , Camundongos , Camundongos Knockout , Gravidez , Pró-Colágeno-Prolina Dioxigenase/genética , Pró-Colágeno-Prolina Dioxigenase/fisiologia , Gânglio Cervical Superior/anormalidades , Gânglio Cervical Superior/patologia , Gânglio Cervical Superior/fisiopatologia , Sistema Nervoso Simpático/patologia , Sistema Nervoso Simpático/fisiopatologiaRESUMO
HIF prolyl hydroxylases (PHD1-3) are oxygen sensors that regulate the stability of the hypoxia-inducible factors (HIFs) in an oxygen-dependent manner. Here, we show that loss of Phd1 lowers oxygen consumption in skeletal muscle by reprogramming glucose metabolism from oxidative to more anaerobic ATP production through activation of a Pparalpha pathway. This metabolic adaptation to oxygen conservation impairs oxidative muscle performance in healthy conditions, but it provides acute protection of myofibers against lethal ischemia. Hypoxia tolerance is not due to HIF-dependent angiogenesis, erythropoiesis or vasodilation, but rather to reduced generation of oxidative stress, which allows Phd1-deficient myofibers to preserve mitochondrial respiration. Hypoxia tolerance relies primarily on Hif-2alpha and was not observed in heterozygous Phd2-deficient or homozygous Phd3-deficient mice. Of medical importance, conditional knockdown of Phd1 also rapidly induces hypoxia tolerance. These findings delineate a new role of Phd1 in hypoxia tolerance and offer new treatment perspectives for disorders characterized by oxidative stress.
