Chronic sodium nitrite therapy augments ischemia-induced angiogenesis and arteriogenesis

Abstract

Chronic tissue ischemia due to defective vascular perfusion is a hallmark feature of peripheral artery disease for which minimal therapeutic options exist. We have reported that sodium nitrite therapy exerts cytoprotective effects against acute ischemia/reperfusion injury in both heart and liver, consistent with the model of bioactive NO formation from nitrite during ischemic stress. Here, we test the hypothesis that chronic sodium nitrite therapy can selectively augment angiogenic activity and tissue perfusion in the murine hind-limb ischemia model. Various therapeutic doses (8.25-3,300 g/kg) of sodium nitrite or PBS were administered. Sodium nitrite significantly restored ischemic hind-limb blood flow in a timedependent manner, with low-dose sodium nitrite being most effective. Nitrite therapy significantly increased ischemic limb vascular density and stimulated endothelial cell proliferation. Remarkably, the effects of sodium nitrite therapy were evident within 3 days of the ischemic insult demonstrating the potency and efficacy of chronic sodium nitrite therapy. Sodium nitrite therapy also increased ischemic tissue nitrite and NO metabolites compared to nonischemic limbs. Use of the NO scavenger carboxy PTIO completely abolished sodium nitrite-dependent ischemic tissue blood flow and angiogenic activity consistent with nitrite reduction to NO being the proangiogenic mechanism. These data demonstrate that chronic sodium nitrite therapy is a recently discovered therapeutic treatment for peripheral artery disease and critical limb ischemia.wound healing ͉ endothelial cell ͉ nitric oxide ͉ peripheral artery disease ͉ tissue perfusion

Mechanisms of hepatic ischemia-reperfusion injury and protective effects of nitric oxide

“…Interventions that increase NO production by the use of sodium nitrite before the occurrence of ischemia, either through intraperitoneal injection or oral administration, can mediate significant cytoprotection. This strategy has been demonstrated to potently limit acute IRI in both the heart and liver in murine warm IRI models, with the ability to decrease myocardial infarction and hepatocyte apoptosis [40][41][42][43] . NO is also an important effector molecule, produced by KCs and dendritic cells (DCs), and is involved in immune regulation and host innate and adaptive immunity [44] .…”

Sodium nitrite in patients with peripheral artery disease and diabetes mellitus: Safety, walking distance and endothelial function

“…[7][8][9] Nitrite is a first-order Sodium nitrite in patients with peripheral artery disease and diabetes mellitus: Safety, walking distance and endothelial function metabolite of NO oxidation and a marker of constitutive NOS activity. More recently, nitrite has been advanced as a circulating NO storage depot and delivery source, reacting with oxyhemoglobin to form nitrate and methemoglobin (MetHb) or with deoxyhemoglobin to form NO, nitrosyl hemoglobin, and other NO adducts.…”

Tissue Processing of Nitrite in Hypoxia

“…More recently, it has become apparent that NO 2 Ϫ , previously considered an inert byproduct of NO metabolism present in plasma (50 -500 nM) and tissues (0.5-25 M), is, under some conditions, also a source of NO/nitrosothiol signaling (6,8). Although the importance of NO 2 Ϫ has received increasing appreciation (9) as being central to processes including exercise (10), hypoxic vasodilation (11), myocardial preconditioning (12,13), and angiogenesis (14), controversy surrounds the chemistry, kinetics, and tissue specificity of NO 2 Ϫ bioactivity (15,16). Perhaps the greatest uncertainty pertains to the role of heme moieties in NO 2 Ϫ metabolism (6,10,12,13,(15)(16)(17)(18)(19)(20)(21)(22).…”