Molecular Alterations in a Mouse Cardiac Model of Friedreich Ataxia: An Impaired Nrf2 Response Mediated via Upregulation of Keap1 and Activation of the Gsk3β Axis

TY - JOUR

T1 - Molecular Alterations in a Mouse Cardiac Model of Friedreich Ataxia

T2 - An Impaired Nrf2 Response Mediated via Upregulation of Keap1 and Activation of the Gsk3β Axis

AU - Anzovino, Amy

AU - Chiang, Shannon

AU - Brown, Bronwyn E

AU - Hawkins, Clare L

AU - Richardson, Des R

AU - Huang, Michael L-H

N1 - Copyright © 2017 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.

PY - 2017/12

Y1 - 2017/12

N2 - Nuclear factor-erythroid 2-related factor-2 (Nrf2) is a master regulator of the antioxidant response. However, studies in models of Friedreich ataxia, a neurodegenerative and cardiodegenerative disease associated with oxidative stress, reported decreased Nrf2 expression attributable to unknown mechanisms. Using a mouse conditional frataxin knockout (KO) model in the heart and skeletal muscle, we examined the Nrf2 pathway in these tissues. Frataxin KO results in fatal cardiomyopathy, whereas skeletal muscle was asymptomatic. In the KO heart, protein oxidation and a decreased glutathione/oxidized glutathione ratio were observed, but the opposite was found in skeletal muscle. Decreased total and nuclear Nrf2 and increased levels of its inhibitor, Kelch-like ECH-associated protein 1, were evident in the KO heart, but not in skeletal muscle. Moreover, a mechanism involving activation of the nuclear Nrf2 export/degradation machinery via glycogen synthase kinase-3β (Gsk3β) signaling was demonstrated in the KO heart. This process involved the following: i) increased Gsk3β activation, ii) β-transducin repeat containing E3 ubiquitin protein ligase nuclear accumulation, and iii) Fyn phosphorylation. A corresponding decrease in Nrf2-DNA-binding activity and a general decrease in Nrf2-target mRNA were observed in KO hearts. Paradoxically, protein levels of some Nrf2 antioxidant targets were significantly increased in KO mice. Collectively, cardiac frataxin deficiency reduces Nrf2 levels via two potential mechanisms: increased levels of cytosolic Kelch-like ECH-associated protein 1 and activation of Gsk3β signaling, which decreases nuclear Nrf2. These findings are in contrast to the frataxin-deficient skeletal muscle, where Nrf2 was not decreased.

AB - Nuclear factor-erythroid 2-related factor-2 (Nrf2) is a master regulator of the antioxidant response. However, studies in models of Friedreich ataxia, a neurodegenerative and cardiodegenerative disease associated with oxidative stress, reported decreased Nrf2 expression attributable to unknown mechanisms. Using a mouse conditional frataxin knockout (KO) model in the heart and skeletal muscle, we examined the Nrf2 pathway in these tissues. Frataxin KO results in fatal cardiomyopathy, whereas skeletal muscle was asymptomatic. In the KO heart, protein oxidation and a decreased glutathione/oxidized glutathione ratio were observed, but the opposite was found in skeletal muscle. Decreased total and nuclear Nrf2 and increased levels of its inhibitor, Kelch-like ECH-associated protein 1, were evident in the KO heart, but not in skeletal muscle. Moreover, a mechanism involving activation of the nuclear Nrf2 export/degradation machinery via glycogen synthase kinase-3β (Gsk3β) signaling was demonstrated in the KO heart. This process involved the following: i) increased Gsk3β activation, ii) β-transducin repeat containing E3 ubiquitin protein ligase nuclear accumulation, and iii) Fyn phosphorylation. A corresponding decrease in Nrf2-DNA-binding activity and a general decrease in Nrf2-target mRNA were observed in KO hearts. Paradoxically, protein levels of some Nrf2 antioxidant targets were significantly increased in KO mice. Collectively, cardiac frataxin deficiency reduces Nrf2 levels via two potential mechanisms: increased levels of cytosolic Kelch-like ECH-associated protein 1 and activation of Gsk3β signaling, which decreases nuclear Nrf2. These findings are in contrast to the frataxin-deficient skeletal muscle, where Nrf2 was not decreased.

KW - Animals

KW - Cardiomyopathies

KW - Disease Models, Animal

KW - Friedreich Ataxia

KW - Glycogen Synthase Kinase 3 beta

KW - Iron-Binding Proteins

KW - Kelch-Like ECH-Associated Protein 1

KW - Mice

KW - Mice, Inbred C57BL

KW - Mice, Knockout

KW - Muscle, Skeletal

KW - Myocardium

KW - NF-E2-Related Factor 2

KW - Oxidative Stress

KW - Up-Regulation

U2 - 10.1016/j.ajpath.2017.08.021

DO - 10.1016/j.ajpath.2017.08.021

M3 - Journal article

C2 - 28935570

SN - 0002-9440

VL - 187

SP - 2858

EP - 2875

JO - American Journal of Pathology

JF - American Journal of Pathology

IS - 12

ER -