Dietary nitrite supplementation protects against myocardial ischemia-reperfusion injury

Abstract

Nitrite has emerged as an endogenous signaling molecule with potential therapeutic implications for cardiovascular disease. Steadystate levels of nitrite are derived in part from dietary sources; therefore, we investigated the effects of dietary nitrite and nitrate supplementation and deficiency on NO homeostasis and on the severity of myocardial ischemia-reperfusion (MI/R) injury. Mice fed a standard diet with supplementation of nitrite (50 mg/liter) in their drinking water for 7 days exhibited significantly higher plasma levels of nitrite, exhibited significantly higher myocardial levels of nitrite, nitroso, and nitrosyl-heme, and displayed a 48% reduction in infarct size (Inf) after MI/R. Supplemental nitrate (1 g/liter) in the drinking water for 7 days also increased blood and tissue NO products and significantly reduced Inf. A time course of ischemia-reperfusion revealed that nitrite was consumed during the ischemic phase, with an increase in nitroso/nitrosyl products in the heart. Mice fed a diet deficient in nitrite and nitrate for 7 days exhibited significantly diminished plasma and heart levels of nitrite and NO metabolites and a 59% increase in Inf after MI/R. Supplementation of nitrite in the drinking water for 7 days reversed the effects of nitrite deficiency. These data demonstrate the significant influence of dietary nitrite and nitrate intake on the maintenance of steady-state tissue nitrite/nitroso levels and illustrate the consequences of nitrite deficiency on the pathophysiology of MI/R injury. Therefore, nitrite and nitrate may serve as essential nutrients for optimal cardiovascular health and may provide a treatment modality for cardiovascular disease.dietary supplementation ͉ myocardial infarction ͉ nitric oxide T he loss of nitric oxide (NO) generation as a result of a dysfunctional vascular endothelium is an often cited correlate of heart disease (1). Continuous generation of NO is essential for the integrity of the cardiovascular system, and a decreased production and/or bioavailability of NO is central to the development of cardiovascular disorders (2, 3). NO is a highly reactive and diffusible gas formed by three NO synthase (NOS) isoforms: neuronal NOS (nNOS), endothelial NOS (eNOS), and inducible NOS (iNOS). NO has been extensively studied in the setting of ischemiareperfusion (I/R) injury. Previous studies clearly demonstrate that the deficiency of eNOS exacerbates myocardial I/R (MI/R) injury (4), whereas the overexpression of eNOS (5, 6), NO donor (7, 8), or inhaled NO gas (9) therapy significantly protect the myocardium (10). NO possesses a number of physiological properties that make it a potent cardioprotective-signaling molecule. These include vasodilation and the inhibition of oxidative stress, platelet aggregation, leukocyte chemotaxis, and apoptosis (11-13). NO synthesis is influenced critically by various cofactors, such as tetrahydrobiopterin, flavin mononucleotide, and flavin adenine dinucleotide, as well as the presence of reduced thiols, the endogenous NOS inhibitor asy...

Globin X is a six-coordinate globin that reduces nitrite to nitric oxide in fish red blood cells

“…The role of nitrite as an exogenous source of NO has gathered increasing attention as it can increase NO bioavailability under physiological hypoxemic conditions and provide beneficial effects in the treatment of cardiovascular diseases (33,34). In this regard, it is now recognized that deoxygenated Hb in mammalian blood can reduce nitrite to NO in vivo, and thus modulate blood pressure, hypoxic vasodilation, mitochondrial respiration and the inhibition of platelet activation (11,35).…”

Construction of effective disposable biosensors for point of care testing of nitrite

“…Endogenous nitrite anions are a major intravascular storage of mammalian nitric oxide, a potent vasodilatory and signaling molecule. Even at low concentrations, nitrite regulates a number of signaling events along the (patho)physiological oxygen gradient including modulation of mitochondrial respiration and cytoprotection following ischemic insult [8][9][10][11]. Unfortunately, the actual circulating levels of nitrite in humans have been difficult to measure due to sampling problems and the poor performance of analytical assays.…”

Role of β-Adrenergic Receptors and Nitric Oxide Signaling in Exercise-Mediated Cardioprotection

“…S-nitrosylation of myocardial target proteins associated with ␤-adrenergic receptor signaling and/or calcium handling influences the contraction of the heart (31,54,69). In regard to pathophysiology, increasing the S-nitrosylation of proteins during myocardial I/R can attenuate a number of adverse processes (10,36,64), such as apoptosis (46) and inflammation (14), and even stimulate protective processes like angiogenesis (45). Specifically, S-nitrosylation of N-ethylmaleimide-sensitive factor inhibits endothelial cell exocytosis and neutrophil infiltration following myocardial I/R (73).…”