Clinical translation of nitrite therapy for cardiovascular diseases

Abstract

The anion nitrite is an oxidative breakdown product of nitric oxide (NO) that has traditionally been viewed as a diagnostic marker of NO formation in biological systems. In this regard, nitrite has long been considered an inert oxidation product of NO metabolism. More recently, this view has changed with the discovery that nitrite represents a physiologically relevant storage reservoir of NO in blood and tissues that can readily be reduced to NO under pathological conditions. This has sparked a renewed interest in the biological role of nitrite and has led to an extensive amount of work investigating its therapeutic potential. As a result, nitrite therapy has now been shown to be cytoprotective in numerous animal models of disease. Given the very robust preclinical data regarding the cytoprotective effects of nitrite therapy it is very logical to consider the clinical translation of nitrite-based therapies. This article will review some of this preclinical data and will discuss the potential use of nitrite therapy as a therapeutic agent for the treatment of cardiovascular diseases including: ischemia-reperfusion injury (i.e. acute myocardial infarction and stroke), hypertension, angiogenesis, and as an adjunctive therapy for transplantation of various organs (i.e. liver and lung).

Diallyl Trisulfide Augments Ischemia-Induced Angiogenesis via an Endothelial Nitric Oxide Synthase-Dependent Mechanism

“…20, 21 The expression and phosphorylation of Akt and eNOS in ischemic adductor muscles of WT mice and non-ischemic adductor muscles of sham mice were assessed by Western blot analysis on postoperative day 3. DATS administration did not alter the phosphorylation of Akt at Thr-308 Figure 2.…”

“…2 The production of H2S is attributed to 3 endogenous enzymes: cystathionine γ -lyase (CGL or CSE), cystathionine β-synthase (CBS), and 3-mercaptopyruvate sulfurtransferase (3MST). 3-5 Recently, it was reported that H2S possesses antioxidant, anti-apoptotic, anti-inflammatory, and mitochondrial-protecting activities in various cell DATS Augments Ischemia-Induced Angiogenesis Histology Ischemic muscles of mice treated with the vehicle control or DATS were collected at postoperative day 21. Frozen sections of 6-μm thickness were prepared using a cryostat (Leica CM3050 S, Leica Biosystems) and stained with an anti-CD31 antibody (Becton Dickinson) to detect capillary ECs.…”

Modulating endothelial nitric oxide synthase: a new cardiovascular therapeutic strategy

“…Exogenous sources, principally environmental pollutants and intake of vegetables, also contribute to this NO reserve. While the anion NO 2 Ϫ has traditionally been considered a mere oxidative breakdown product of NO and a diagnostic marker of its formation at nanomolar concentrations in biological systems, more recent discoveries indicate that NO 2 Ϫ represents a physiologically relevant storage reservoir of NO in blood and tissues with distinct signaling functions at nearphysiological concentrations (19). The NO 2 Ϫ anion can be readily reduced to bioactive NO along a physiological oxygen and pH gradient either nonenzymatically (167) or by a number of enzymes, including XORs, NOS, mitochondrial cytochromes, and deoxygenated hemoglobin and myoglobin (25,71,72,122,140).…”

“…However, the major concern of such a strategy remains the potential risk of inadvertent systemic vasodilation and hypotension caused by circulating NO 2 Ϫ reductases. Currently, there are several clinical studies underway to investigate safety, i.e., methemoglobin formation and inadvertent hypotension, and potential therapeutic efficacy of NO 2 Ϫ administration in patients with acute myocardial infarction, cerebral vasospasm, and pulmonary hypertension (19). When NO 2 Ϫ is administered during noninflammatory states, one of the mechanisms thought to mediate the beneficial effects is that nitrites are stored in erytrocytes and can be secondarily reduced to vasoactive NO by, e.g., XORs under anaerobic conditions (10).…”

Nitrite Therapy Ameliorates Myocardial Dysfunction via H 2 S and Nuclear Factor‐Erythroid 2‐Related Factor 2 (Nrf2)‐Dependent Signaling in Chronic Heart Failure

“…In addition, experimental studies have shown that enhancing NO levels through genetic manipulation leads to improved survival,12 decreased remodeling,16 and improved cardiac function following ischemia‐induced HF in mice. Among NO donors, sodium nitrite (NaNO 2 ) represents a promising therapeutic agent for the treatment of HF,17 being an attractive candidate for restoring physiological NO signaling in states of chronic NO insufficiency such as myocardial ischemia. NaNO 2 is rapidly absorbed from the circulation by peripheral tissues and stored in cells until conversion to NO is needed 18, 19, 20.…”