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

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 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.

Natural mutations of human XDH promote the nitrite (NO2−)-reductase capacity of xanthine oxidoreductase: A novel mechanism to promote redox health?

“…The functional remit of XOR has extended well beyond ROS and UA synthesis over the past 10–15 years, with the growing appreciation that in many pathological settings, particularly for metabolic disease and CVD, when the eNOS-dependent pathway is dysfunctional, XOR acts as a critical NO 2 − -reductase [ 9 ], [ [64] , [65] , [66] ]. Thus, the increase in NO 2 − reduction to ·NO observed in this study with some of the naturally occurring mutations may be particularly important for health.…”

Probabilistic Risk of Nitrates to Human Health Via Drinking Water: A Case Study of Water Supply for Dandan Station and its Quarters in Mosul, Iraq

“…This process plays a crucial role in the regulation and reduction of systolic blood pressure, contributing to the prevention of various cardiovascular diseases. 41,42 Conclusions and Recommendations This is one of the few rare studies in Iraq that has examined the potential health risks associated with nitrates. Our findings revealed that the nitrate level in the drinking water supplied to Dandan station was significantly below the global permissible limits.…”

Exosomes derived from adipose tissue-derived stem cells alleviated H2O2-induced oxidative stress and endothelial-to-mesenchymal transition in human umbilical vein endothelial cells by inhibition of the mir-486-3p/Sirt6/Smad signaling pathway

“…The reduction of H 2 O 2 in mouse models of cardiac remodeling resulted in a decrease in cardiac fibrosis through the NO-mediated inhibition of phosphorylated Smad (Gee et al 2022 ), and the conditioned medium of MSCs partially regulated the Smad pathway to attenuate oxidative stress injury in hepatocytes (Ma et al 2021 ). The Sirt6-deficiency fibroblasts exhibited spontaneous trans-differentiation into myofibroblasts, which was attributed to the hyperactivation of TGFβ/Smad signaling, the aberrant activation further led to an induction of fibrosis in mice (Maity et al 2020 ).…”