Long-term dietary nitrite and nitrate deficiency causes metabolic syndrome, endothelial dysfunction, and cardiovascular death in mice

Abstract

Nitric oxide (NO) is synthesized not only from L-arginine by NO synthases (NOSs), but also from its inert metabolites, nitrite and nitrate. Green leafy vegetables are abundant in nitrate, however whether or not a deficiency in dietary nitrite/nitrate spontaneously causes disease remains to be clarified. In this study, we tested our hypothesis that long-term dietary nitrite/nitrate deficiency induces metabolic syndrome (MetS) in mice. To this end, we prepared a low nitrite/nitrate diet (LND) consisting of an amino acid-based low nitrite/nitrate chow in which the contents of L-arginine, fat, carbohydrates, protein, and energy were identical with a regular chow, and potable ultrapure water. Nitrite and nitrate were undetectable in both the chow and the water. Intriguingly, in comparison with a regular diet, 3 months of the LND significantly elicited visceral adiposity, dyslipidaemia, and glucose intolerance; 18 months of the LND significantly provoked increased body weight, hypertension, insulin resistance, and impaired endothelium-dependent relaxations to acetylcholine; and 22 months of the LND significantly led to death due to cardiovascular disease, including acute myocardial infarction. These abnormalities were reversed by simultaneous treatment with sodium nitrate, and were significantly associated with endothelial NOS down-regulation, adiponectin insufficiency, and gut microbiota dysbiosis. These results provide the first evidence that long-term dietary nitrite/nitrate deficiency gives rise to MetS, endothelial dysfunction, and cardiovascular death in mice, indicating a novel pathogenetic role of the exogenous NO production system in MetS and its vascular complications.

Exposure to a “safe” dose of environmental pollutant bisphenol A elevates oxidative stress and modulates vasoactive system in hypertensive rats

“…While considering the impact on NO level, long-term dietary nitrite and nitrate deficiency causes metabolic syndrome, endothelial dysfunction, and cardiovascular death in mice. 40 Moreover, BPA induces endothelial cell necroptosis and promotes the weakening of the coronary vascular wall that ultimately leads to cardiac dysfunction. 41 Precisely, oral administration of BPA induces high blood pressure through angiotensin II/CaMKII–dependent uncoupling of eNOS.…”

Development of Novel Therapies for Cardiovascular Diseases by Clinical Application of Basic Research

“…2,3,12 AMPK/eNOS signaling plays a crucial role in vascular homeostasis and E ndothelial cells (ECs) secrete a variety of vasoactive substances, 1-4 such as nitric oxide (NO), prostacyclin, and hydrogen peroxide (H2O2), that protect against vascular dysfunction and organ failure. 5, 6 These substances affect adjacent vascular smooth muscle cells (VSMCs) to activate downstream signaling elements, including soluble guanylyl cyclase (sGC)/cGMP, adenylate cyclase/cAMP, and cGMP-dependent protein kinase 1-α (PKG1α), effecting vascular relaxation. 7 In contrast, the RhoA/Rho-kinase pathway plays an important role in various fundamental cellular functions, including contraction, motility, and proliferation of VSMCs, affecting vascular contraction and remodeling.…”

Inorganic Nitrate Promotes Glucose Uptake and Oxidative Catabolism in White Adipose Tissue Through the XOR-Catalyzed Nitric Oxide Pathway

“…Complementary studies of dietary nitrate administration to the eNOS-deficient mouse and Sprague-Dawley rats report reduced adiposity and improved glucose and insulin homeostasis following nitrate treatment (4; 5). Inversely, long-term dietary nitrate deficiency induced the metabolic syndrome in mice (6). Therefore, nitrate may provide a therapeutic avenue for the treatment of aspects of the metabolic syndrome.…”