Kumar Dinesh, Branch Billy G, Pattillo Christopher B, Hood Jay, Thoma Stephen, Simpson Stephen, Illum Sandra, Arora Neeraj, Chidlow John H, Langston Will, Teng Xinjun, Lefer David J, Patel Rakesh P, Kevil Christopher G
Departments of Pathology and Cardiology, Louisiana State University Health Sciences Center, Shreveport, LA 71130, USA.
Proc Natl Acad Sci U S A. 2008 May 27;105(21):7540-5. doi: 10.1073/pnas.0711480105.
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 mug/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.
由于血管灌注缺陷导致的慢性组织缺血是外周动脉疾病的一个标志性特征，针对该疾病的治疗选择极少。我们曾报道，亚硝酸钠疗法对心脏和肝脏的急性缺血/再灌注损伤均具有细胞保护作用，这与缺血应激期间由亚硝酸盐形成生物活性一氧化氮（NO）的模型一致。在此，我们检验以下假设：在小鼠后肢缺血模型中，慢性亚硝酸钠疗法可选择性增强血管生成活性并改善组织灌注。给予不同治疗剂量（8.25 - 3300微克/千克）的亚硝酸钠或磷酸盐缓冲液（PBS）。亚硝酸钠能以时间依赖性方式显著恢复缺血后肢的血流，低剂量亚硝酸钠最为有效。亚硝酸盐疗法显著增加了缺血肢体的血管密度并刺激了内皮细胞增殖。值得注意的是，在缺血损伤后3天内，亚硝酸钠疗法的效果就很明显，这表明了慢性亚硝酸钠疗法的效力和功效。与非缺血肢体相比，亚硝酸钠疗法还增加了缺血组织中的亚硝酸盐和NO代谢产物。使用NO清除剂羧基-PTIO完全消除了亚硝酸钠依赖性的缺血组织血流和血管生成活性，这与亚硝酸盐还原为NO是促血管生成机制一致。这些数据表明，慢性亚硝酸钠疗法是最近发现的一种用于治疗外周动脉疾病和严重肢体缺血的治疗方法。
