Chronic sodium nitrite therapy augments ischemia-induced angiogenesis and arteriogenesis
Published online on May 27, 2008, 10.1073/pnas.0711480105 OPEN ACCESS ARTICLE
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Dinesh Kumar*, Billy G. Branch{dagger}, Christopher B. Pattillo{dagger}, Jay Hood{dagger}, Stephen Thoma{dagger}, Stephen Simpson*, Sandra Illum*, Neeraj Arora*, John H. Chidlow, Jr.{dagger}, Will Langston{dagger}, Xinjun Teng{ddagger}, David J. Lefer§, Rakesh P. Patel{ddagger}, and Christopher G. Kevil{dagger},¶
Departments of {dagger}Pathology and *Cardiology, Louisiana State University Health Sciences Center, Shreveport, LA 71130; {ddagger}Department of Pathology and Center for Free Radical Biology, University of Alabama, Birmingham, AL 35294; and §Department of Cardiology, Albert Einstein College of Medicine, Bronx, NY 10461
Edited by Louis J. Ignarro, University of California School of Medicine, Los Angeles, CA, and approved March 21, 2008 (received for review December 6, 2007)
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 µg/kg) of sodium nitrite or PBS were administered. Sodium nitrite significantly restored ischemic hind-limb blood flow in a time-dependent 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. |
