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Inorganic nitrate attenuates cardiac dysfunction: roles for xanthine oxidoreductase and nitric oxide

Gee, LC; Massimo, G; Lau, C; Primus, C; Fernandes, D; Chen, J; Rathod, KS; ... Ahluwalia, A; + view all (2021) Inorganic nitrate attenuates cardiac dysfunction: roles for xanthine oxidoreductase and nitric oxide. British Journal of Pharmacology 10.1111/bph.15636. (In press). Green open access

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Abstract

Nitric oxide (NO) is a vasodilator and independent modulator of cardiac remodelling. Commonly, in cardiac disease (e.g. heart failure) endothelial dysfunction (synonymous with NO-deficiency) has been implicated in increased blood pressure (BP), cardiac hypertrophy and fibrosis. Currently no effective therapies replacing NO have succeeded in the clinic. Inorganic nitrate (NO3 - ), through chemical reduction to nitrite and then NO, exerts potent BP-lowering but whether it might be useful in treating undesirable cardiac remodelling is unknown. In a nested age- and sex-matched case-control study of hypertensive patients +/- left ventricular hypertrophy (NCT03088514) we show that lower plasma nitrite concentration and vascular dysfunction accompany cardiac hypertrophy and fibrosis in patients. In mouse models of cardiac remodelling, we also show that restoration of circulating nitrite levels using dietary nitrate improves endothelial dysfunction through targeting of xanthine oxidoreductase (XOR)-driven H2 O2 and superoxide, and reduces cardiac fibrosis through NO-mediated block of SMAD-phosphorylation leading to improvements in cardiac structure and function. We show that via these mechanisms dietary nitrate offers easily translatable therapeutic options for treatment of cardiac dysfunction.

Type: Article
Title: Inorganic nitrate attenuates cardiac dysfunction: roles for xanthine oxidoreductase and nitric oxide
Location: England
Open access status: An open access version is available from UCL Discovery
DOI: 10.1111/bph.15636
Publisher version: https://doi.org/10.1111/bph.15636
Language: English
Additional information: Copyright © 2021 The Authors. British Journal of Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society. This is an open access article under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/), which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
Keywords: Heart failure, Hypertension, Nitrate, Nitric oxide, Oxidative stress, Xanthine oxidoreductase
UCL classification: UCL
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > Institute of Cardiovascular Science
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > Institute of Cardiovascular Science > Clinical Science
URI: https://discovery.ucl.ac.uk/id/eprint/10135902
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