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The NRF2 knockout rat: a new animal model to study endothelial dysfunction, oxidant stress, and microvascular rarefaction. Am J Physiol Heart Circ Physiol 2016 Feb 15;310(4):H478-87

Date

12/08/2015

Pubmed ID

26637559

Pubmed Central ID

PMC4796617

DOI

10.1152/ajpheart.00586.2015

Scopus ID

2-s2.0-84958559081   22 Citations

Abstract

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.

Author List

Priestley JR, Kautenburg KE, Casati MC, Endres BT, Geurts AM, Lombard JH

Authors

Aron Geurts PhD Associate Professor in the Physiology department at Medical College of Wisconsin
Julian H. Lombard PhD Professor in the Physiology department at Medical College of Wisconsin




MESH terms used to index this publication - Major topics in bold

Acetylcholine
Angiotensin II
Animals
Antioxidants
Capillaries
Endothelium, Vascular
Gene Knockout Techniques
Immunohistochemistry
Microcirculation
Middle Cerebral Artery
NF-E2-Related Factor 2
Oxidative Stress
Rats
Rats, Sprague-Dawley
Translocation, Genetic
Up-Regulation
Vasoconstrictor Agents
Vasodilator Agents
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