Inorganic nitrate attenuates cardiac dysfunction: role for xanthine oxidoreductase and nitric oxide
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DOI
10.1111/bph.15636
Journal
British Journal of Pharmacology
ISSN
0007-1188
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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 H2O2 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.