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Original Article

Nicotinamide Adenine Dinucleotide Phosphate Oxidase-4–Dependent Upregulation of Nuclear Factor Erythroid–Derived 2-Like 2 Protects the Heart During Chronic Pressure Overload

Ioannis Smyrnias, Xiaohong Zhang, Min Zhang, Thomas V.A. Murray, Ralf P. Brandes, Katrin Schröder, Alison C. Brewer, Ajay M. Shah
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https://doi.org/10.1161/HYPERTENSIONAHA.114.04208
Hypertension. 2014;HYPERTENSIONAHA.114.04208
Originally published December 22, 2014
Ioannis Smyrnias
From the Department of Cardiology, Cardiovascular Division, King’s College London British Heart Foundation Centre, London, United Kingdom (I.S., X.Z., M.Z., T.V.A.M., A.C.B., A.M.S.); and Vascular Research Centre, Institute for Cardiovascular Physiology, Goethe-University, Frankfurt, Germany (R.P.B., K.S.).
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Xiaohong Zhang
From the Department of Cardiology, Cardiovascular Division, King’s College London British Heart Foundation Centre, London, United Kingdom (I.S., X.Z., M.Z., T.V.A.M., A.C.B., A.M.S.); and Vascular Research Centre, Institute for Cardiovascular Physiology, Goethe-University, Frankfurt, Germany (R.P.B., K.S.).
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Min Zhang
From the Department of Cardiology, Cardiovascular Division, King’s College London British Heart Foundation Centre, London, United Kingdom (I.S., X.Z., M.Z., T.V.A.M., A.C.B., A.M.S.); and Vascular Research Centre, Institute for Cardiovascular Physiology, Goethe-University, Frankfurt, Germany (R.P.B., K.S.).
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Thomas V.A. Murray
From the Department of Cardiology, Cardiovascular Division, King’s College London British Heart Foundation Centre, London, United Kingdom (I.S., X.Z., M.Z., T.V.A.M., A.C.B., A.M.S.); and Vascular Research Centre, Institute for Cardiovascular Physiology, Goethe-University, Frankfurt, Germany (R.P.B., K.S.).
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Ralf P. Brandes
From the Department of Cardiology, Cardiovascular Division, King’s College London British Heart Foundation Centre, London, United Kingdom (I.S., X.Z., M.Z., T.V.A.M., A.C.B., A.M.S.); and Vascular Research Centre, Institute for Cardiovascular Physiology, Goethe-University, Frankfurt, Germany (R.P.B., K.S.).
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Katrin Schröder
From the Department of Cardiology, Cardiovascular Division, King’s College London British Heart Foundation Centre, London, United Kingdom (I.S., X.Z., M.Z., T.V.A.M., A.C.B., A.M.S.); and Vascular Research Centre, Institute for Cardiovascular Physiology, Goethe-University, Frankfurt, Germany (R.P.B., K.S.).
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Alison C. Brewer
From the Department of Cardiology, Cardiovascular Division, King’s College London British Heart Foundation Centre, London, United Kingdom (I.S., X.Z., M.Z., T.V.A.M., A.C.B., A.M.S.); and Vascular Research Centre, Institute for Cardiovascular Physiology, Goethe-University, Frankfurt, Germany (R.P.B., K.S.).
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Ajay M. Shah
From the Department of Cardiology, Cardiovascular Division, King’s College London British Heart Foundation Centre, London, United Kingdom (I.S., X.Z., M.Z., T.V.A.M., A.C.B., A.M.S.); and Vascular Research Centre, Institute for Cardiovascular Physiology, Goethe-University, Frankfurt, Germany (R.P.B., K.S.).
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Abstract

The transcription factor nuclear factor erythroid–derived 2-like 2 (Nrf2) controls a network of cytoprotective genes. Neither how Nrf2 is activated in the heart under hemodynamic overload nor its role and mechanism of action are known. This study aimed to investigate the activation and role of Nrf2 during chronic cardiac pressure overload. We first compared the responses of Nrf2−/− mice and wild-type littermates to chronic pressure overload. Hearts of Nrf2−/− mice showed impaired antioxidant gene expression, increased hypertrophy, and worse function compared with those of wild-type littermates after overload. Hearts of Nrf2−/− mice had increased mitochondrial DNA damage, a caspase 8/BH3-interacting domain death agonist–related cleavage of mitochondrial apoptosis–inducing factor, nuclear DNA damage, and cell death. Nrf2 activation was under the control of the endogenous reactive oxygen species–generating enzyme nicotinamide adenine dinucleotide phosphate oxidase-4, both in vivo and in vitro. In mice with cardiac-specific overexpression of nicotinamide adenine dinucleotide phosphate oxidase-4, Nrf2 deletion significantly attenuated their protective phenotype during chronic pressure overload. This study identifies nicotinamide adenine dinucleotide phosphate oxidase-4–dependent upregulation of Nrf2 as an important endogenous protective pathway that limits mitochondrial damage and apoptosis-inducing factor–related cell death in the heart under hemodynamic overload.

  • cell death
  • Nfe2l2 protein, mouse
  • Nox4 protein, mouse
  • oxidative stress
  • Received July 7, 2014.
  • Revision received July 20, 2014.
  • Accepted November 5, 2014.
  • © 2014 American Heart Association, Inc.
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    Nicotinamide Adenine Dinucleotide Phosphate Oxidase-4–Dependent Upregulation of Nuclear Factor Erythroid–Derived 2-Like 2 Protects the Heart During Chronic Pressure Overload
    Ioannis Smyrnias, Xiaohong Zhang, Min Zhang, Thomas V.A. Murray, Ralf P. Brandes, Katrin Schröder, Alison C. Brewer and Ajay M. Shah
    Hypertension. 2014;HYPERTENSIONAHA.114.04208, originally published December 22, 2014
    https://doi.org/10.1161/HYPERTENSIONAHA.114.04208

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    Nicotinamide Adenine Dinucleotide Phosphate Oxidase-4–Dependent Upregulation of Nuclear Factor Erythroid–Derived 2-Like 2 Protects the Heart During Chronic Pressure Overload
    Ioannis Smyrnias, Xiaohong Zhang, Min Zhang, Thomas V.A. Murray, Ralf P. Brandes, Katrin Schröder, Alison C. Brewer and Ajay M. Shah
    Hypertension. 2014;HYPERTENSIONAHA.114.04208, originally published December 22, 2014
    https://doi.org/10.1161/HYPERTENSIONAHA.114.04208
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