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Cardiac-targeted NADPH oxidase 4 in the adaptive cardiac remodelling of the murine heart

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Cardiac-targeted NADPH oxidase 4 in the adaptive cardiac remodelling of the murine heart. / Nabeebaccus, Adam; Hafstad, Anne; Eykyn, Tom; Yin, Xiaoke; Brewer, Alison; Zhang, Min; Mayr, Manuel; Shah, Ajay.

In: Lancet, Vol. 385 Suppl 1, 26.02.2015, p. S73.

Research output: Contribution to journalArticle

Harvard

Nabeebaccus, A, Hafstad, A, Eykyn, T, Yin, X, Brewer, A, Zhang, M, Mayr, M & Shah, A 2015, 'Cardiac-targeted NADPH oxidase 4 in the adaptive cardiac remodelling of the murine heart', Lancet, vol. 385 Suppl 1, pp. S73. https://doi.org/10.1016/S0140-6736(15)60388-9

APA

Nabeebaccus, A., Hafstad, A., Eykyn, T., Yin, X., Brewer, A., Zhang, M., ... Shah, A. (2015). Cardiac-targeted NADPH oxidase 4 in the adaptive cardiac remodelling of the murine heart. Lancet, 385 Suppl 1, S73. https://doi.org/10.1016/S0140-6736(15)60388-9

Vancouver

Nabeebaccus A, Hafstad A, Eykyn T, Yin X, Brewer A, Zhang M et al. Cardiac-targeted NADPH oxidase 4 in the adaptive cardiac remodelling of the murine heart. Lancet. 2015 Feb 26;385 Suppl 1:S73. https://doi.org/10.1016/S0140-6736(15)60388-9

Author

Nabeebaccus, Adam ; Hafstad, Anne ; Eykyn, Tom ; Yin, Xiaoke ; Brewer, Alison ; Zhang, Min ; Mayr, Manuel ; Shah, Ajay. / Cardiac-targeted NADPH oxidase 4 in the adaptive cardiac remodelling of the murine heart. In: Lancet. 2015 ; Vol. 385 Suppl 1. pp. S73.

Bibtex Download

@article{1d03b6f3bf3743c89256f81fbdc73285,
title = "Cardiac-targeted NADPH oxidase 4 in the adaptive cardiac remodelling of the murine heart",
abstract = "BACKGROUND: The mechanisms that determine whether the heart adapts to overload stress, or fails, are poorly understood. NADPH oxidase (NOX) proteins produce reactive oxygen species (ROS) involved in redox signalling, and our recent studies have found that an increase in Nox4 during pressure overload protects the heart against failure. We aimed to identify novel Nox4-driven cardioprotective mechanisms that promote adaptive cardiac remodelling.METHODS: We first undertook a proteomic comparison of heart tissue from cardiac-targeted Nox4-overexpressing mice and controls. The Nox4 cardiac metabolome was then investigated by (1)H nuclear magnetic resonance (NMR) spectroscopy. Effects on cardiac metabolism were assessed by ex-vivo working heart perfusions and isolated mitochondrial respiration studies. Ex-vivo cardiac energetics were assessed by (31)P NMR. Alterations to cardiac fatty acid oxidation were explored in primary cardiomyocytes (extracellular flux analysis).FINDINGS: Cardiac-targeted Nox4 overexpression profoundly remodelled the cardiac proteome in an isoform-specific manner, both in the unstressed and stressed heart. Glycolysis and fatty acid oxidation were identified as the most enriched pathways that were altered by Nox4. Metabolomic analysis showed a 2·2 times increase in acetylcarnitine concentrations (p=0·002). Ex-vivo heart perfusions demonstrated a profound increase in palmitate oxidation relative to wild-type hearts (3·6 times increase, p=0·01), with opposite findings observed in primary cardiomyocytes with a knockdown of Nox4. A preference for fatty acid oxidation in Nox4 hearts correlated with a better energetic state (phosphocreatine:ATP ratio) when subjected to increasing doses of isoprenaline stress under baseline and pressure-overload.INTERPRETATION: In this study we identified a novel role for Nox4 in the regulation of cardiac fatty acid oxidation. Cardiomyocyte-targeted Nox4 hearts preferentially oxidised fatty acids for energy provision, improving myocardial energetics under stress. Enhancing fatty acid oxidation might have an adaptive role in the setting of pressure-overload hypertrophy. These data provide novel insights into ROS-dependent metabolic programming.FUNDING: UK Medical Research Council, British Heart Foundation.",
author = "Adam Nabeebaccus and Anne Hafstad and Tom Eykyn and Xiaoke Yin and Alison Brewer and Min Zhang and Manuel Mayr and Ajay Shah",
note = "Copyright {\circledC} 2015 Elsevier Ltd. All rights reserved.",
year = "2015",
month = "2",
day = "26",
doi = "10.1016/S0140-6736(15)60388-9",
language = "English",
volume = "385 Suppl 1",
pages = "S73",
journal = "Lancet",
issn = "0140-6736",
publisher = "Elsevier",

}

RIS (suitable for import to EndNote) Download

TY - JOUR

T1 - Cardiac-targeted NADPH oxidase 4 in the adaptive cardiac remodelling of the murine heart

AU - Nabeebaccus, Adam

AU - Hafstad, Anne

AU - Eykyn, Tom

AU - Yin, Xiaoke

AU - Brewer, Alison

AU - Zhang, Min

AU - Mayr, Manuel

AU - Shah, Ajay

N1 - Copyright © 2015 Elsevier Ltd. All rights reserved.

PY - 2015/2/26

Y1 - 2015/2/26

N2 - BACKGROUND: The mechanisms that determine whether the heart adapts to overload stress, or fails, are poorly understood. NADPH oxidase (NOX) proteins produce reactive oxygen species (ROS) involved in redox signalling, and our recent studies have found that an increase in Nox4 during pressure overload protects the heart against failure. We aimed to identify novel Nox4-driven cardioprotective mechanisms that promote adaptive cardiac remodelling.METHODS: We first undertook a proteomic comparison of heart tissue from cardiac-targeted Nox4-overexpressing mice and controls. The Nox4 cardiac metabolome was then investigated by (1)H nuclear magnetic resonance (NMR) spectroscopy. Effects on cardiac metabolism were assessed by ex-vivo working heart perfusions and isolated mitochondrial respiration studies. Ex-vivo cardiac energetics were assessed by (31)P NMR. Alterations to cardiac fatty acid oxidation were explored in primary cardiomyocytes (extracellular flux analysis).FINDINGS: Cardiac-targeted Nox4 overexpression profoundly remodelled the cardiac proteome in an isoform-specific manner, both in the unstressed and stressed heart. Glycolysis and fatty acid oxidation were identified as the most enriched pathways that were altered by Nox4. Metabolomic analysis showed a 2·2 times increase in acetylcarnitine concentrations (p=0·002). Ex-vivo heart perfusions demonstrated a profound increase in palmitate oxidation relative to wild-type hearts (3·6 times increase, p=0·01), with opposite findings observed in primary cardiomyocytes with a knockdown of Nox4. A preference for fatty acid oxidation in Nox4 hearts correlated with a better energetic state (phosphocreatine:ATP ratio) when subjected to increasing doses of isoprenaline stress under baseline and pressure-overload.INTERPRETATION: In this study we identified a novel role for Nox4 in the regulation of cardiac fatty acid oxidation. Cardiomyocyte-targeted Nox4 hearts preferentially oxidised fatty acids for energy provision, improving myocardial energetics under stress. Enhancing fatty acid oxidation might have an adaptive role in the setting of pressure-overload hypertrophy. These data provide novel insights into ROS-dependent metabolic programming.FUNDING: UK Medical Research Council, British Heart Foundation.

AB - BACKGROUND: The mechanisms that determine whether the heart adapts to overload stress, or fails, are poorly understood. NADPH oxidase (NOX) proteins produce reactive oxygen species (ROS) involved in redox signalling, and our recent studies have found that an increase in Nox4 during pressure overload protects the heart against failure. We aimed to identify novel Nox4-driven cardioprotective mechanisms that promote adaptive cardiac remodelling.METHODS: We first undertook a proteomic comparison of heart tissue from cardiac-targeted Nox4-overexpressing mice and controls. The Nox4 cardiac metabolome was then investigated by (1)H nuclear magnetic resonance (NMR) spectroscopy. Effects on cardiac metabolism were assessed by ex-vivo working heart perfusions and isolated mitochondrial respiration studies. Ex-vivo cardiac energetics were assessed by (31)P NMR. Alterations to cardiac fatty acid oxidation were explored in primary cardiomyocytes (extracellular flux analysis).FINDINGS: Cardiac-targeted Nox4 overexpression profoundly remodelled the cardiac proteome in an isoform-specific manner, both in the unstressed and stressed heart. Glycolysis and fatty acid oxidation were identified as the most enriched pathways that were altered by Nox4. Metabolomic analysis showed a 2·2 times increase in acetylcarnitine concentrations (p=0·002). Ex-vivo heart perfusions demonstrated a profound increase in palmitate oxidation relative to wild-type hearts (3·6 times increase, p=0·01), with opposite findings observed in primary cardiomyocytes with a knockdown of Nox4. A preference for fatty acid oxidation in Nox4 hearts correlated with a better energetic state (phosphocreatine:ATP ratio) when subjected to increasing doses of isoprenaline stress under baseline and pressure-overload.INTERPRETATION: In this study we identified a novel role for Nox4 in the regulation of cardiac fatty acid oxidation. Cardiomyocyte-targeted Nox4 hearts preferentially oxidised fatty acids for energy provision, improving myocardial energetics under stress. Enhancing fatty acid oxidation might have an adaptive role in the setting of pressure-overload hypertrophy. These data provide novel insights into ROS-dependent metabolic programming.FUNDING: UK Medical Research Council, British Heart Foundation.

U2 - 10.1016/S0140-6736(15)60388-9

DO - 10.1016/S0140-6736(15)60388-9

M3 - Article

C2 - 26312895

VL - 385 Suppl 1

SP - S73

JO - Lancet

JF - Lancet

SN - 0140-6736

ER -

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