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The NRF2 knockout rat: a new animal model to study endothelial dysfunction, oxidant stress, and microvascular rarefaction.
Priestley, Jessica R C; Kautenburg, Katie E; Casati, Marc C; Endres, Bradley T; Geurts, Aron M; Lombard, Julian H.
Afiliación
  • Priestley JR; Department of Physiology, Medical College of Wisconsin, Milwaukee, Wisconsin; and.
  • Kautenburg KE; Department of Physiology, Medical College of Wisconsin, Milwaukee, Wisconsin; and.
  • Casati MC; Department of Physiology, Medical College of Wisconsin, Milwaukee, Wisconsin; and.
  • Endres BT; Department of Physiology, Medical College of Wisconsin, Milwaukee, Wisconsin; and.
  • Geurts AM; Department of Physiology, Medical College of Wisconsin, Milwaukee, Wisconsin; and Human and Molecular Genetics Center, Medical College of Wisconsin, Milwaukee, Wisconsin.
  • Lombard JH; Department of Physiology, Medical College of Wisconsin, Milwaukee, Wisconsin; and jlombard@mcw.edu.
Am J Physiol Heart Circ Physiol ; 310(4): H478-87, 2016 Feb 15.
Article en En | MEDLINE | ID: mdl-26637559
Nuclear factor (erythroid-derived 2)-like-2 (NRF2) is a master antioxidant and cell protective transcription factor that upregulates antioxidant defenses. In this study we developed a strain of Nrf2 null mutant rats to evaluate the role of reduced NRF2-regulated antioxidant defenses in contributing to endothelial dysfunction and impaired angiogenic responses during salt-induced ANG II suppression. Nrf2(-/-) mutant rats were developed using transcription activator-like effector nuclease technology in the Sprague-Dawley genetic background, and exhibited a 41-bp deletion that included the start codon for Nrf2 and an absence of immunohistochemically detectable NRF2 protein. Expression of mRNA for the NRF2-regulated indicator enzymes heme oxygenase-1, catalase, superoxide dismutase 1, superoxide dismutase 2, and glutathione reductase was significantly lower in livers of Nrf2(-/-) mutant rats fed high salt (HS; 4% NaCl) for 2 wk compared with wild-type controls. Endothelium-dependent dilation to acetylcholine was similar in isolated middle cerebral arteries (MCA) of Nrf2(-/-) mutant rats and wild-type littermates fed low-salt (0.4% NaCl) diet, and was eliminated by short-term (3 days) HS diet in both strains. Low-dose ANG II infusion (100 ng/kg sc) reversed salt-induced endothelial dysfunction in MCA and prevented microvessel rarefaction in wild-type rats fed HS diet, but not in Nrf2(-/-) mutant rats. The results of this study indicate that suppression of NRF2 antioxidant defenses plays an essential role in the development of salt-induced oxidant stress, endothelial dysfunction, and microvessel rarefaction in normotensive rats and emphasize the potential therapeutic benefits of directly upregulating NRF2-mediated antioxidant defenses to ameliorate vascular oxidant stress in humans.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Endotelio Vascular / Estrés Oxidativo / Factor 2 Relacionado con NF-E2 / Microcirculación Tipo de estudio: Prognostic_studies Límite: Animals Idioma: En Revista: Am J Physiol Heart Circ Physiol Asunto de la revista: CARDIOLOGIA / FISIOLOGIA Año: 2016 Tipo del documento: Article Pais de publicación: Estados Unidos
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Endotelio Vascular / Estrés Oxidativo / Factor 2 Relacionado con NF-E2 / Microcirculación Tipo de estudio: Prognostic_studies Límite: Animals Idioma: En Revista: Am J Physiol Heart Circ Physiol Asunto de la revista: CARDIOLOGIA / FISIOLOGIA Año: 2016 Tipo del documento: Article Pais de publicación: Estados Unidos