title: Nicotinamide adenine dinucleotide phosphate oxidase-4-dependent upregulation of nuclear factor erythroid-derived 2-like 2 protects the heart during chronic pressure overload.
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.
authors.affiliation: 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.).
authors.forename: Ioannis
authors.initials: I
authors.lastname: Smyrnias
authors.affiliation: 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.).
authors.forename: Xiaohong
authors.initials: X
authors.lastname: Zhang
authors.affiliation: 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.).
authors.forename: Min
authors.initials: M
authors.lastname: Zhang
authors.affiliation: 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.).
authors.forename: Thomas V A
authors.initials: TV
authors.lastname: Murray
authors.affiliation: 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.).
authors.forename: Ralf P
authors.initials: RP
authors.lastname: Brandes
authors.affiliation: 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.).
authors.forename: Katrin
authors.initials: K
authors.lastname: Schröder
authors.affiliation: 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.).
authors.forename: Alison C
authors.initials: AC
authors.lastname: Brewer
authors.affiliation: 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.). ajay.shah@kcl.ac.uk.
authors.forename: Ajay M
authors.initials: AM
authors.lastname: Shah
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000502:physiology; D053148:Caspase 3 / Q000502:physiology; D004249:DNA Damage / Q000502:physiology; D004272:DNA, Mitochondrial / Q000235:genetics; D004195:Disease Models, Animal; D006321:Heart / Q000503:physiopathology*; D006439:Hemodynamics / Q000502:physiology; D006973:Hypertension / Q000473:pathology / Q000503:physiopathology*; D066298:In Vitro Techniques; D051379:Mice; D018345:Mice, Knockout; D032383:Myocytes, Cardiac / Q000473:pathology; D000074663:NADPH Oxidase 4; D019255:NADPH Oxidases / Q000502:physiology*; D051267:NF-E2-Related Factor 2 / Q000172:deficiency / Q000502:physiology*; D015854:Up-Regulation / Q000502:physiology*
chemical_list: D004272:DNA, Mitochondrial; D051267:NF-E2-Related Factor 2; C495636:Nfe2l2 protein, mouse; D000074663:NADPH Oxidase 4; D019255:NADPH Oxidases; C422943:Nox4 protein, mouse; D053148:Caspase 3
keywords: Nfe2l2 protein, mouse; Nox4 protein, mouse; cell death; oxidative stress