New Thoughts in an Old Player: Role of Nitrite in the Treatment of Ischemic Revascularization

  1. James R. Sowers1,2,3,4
  1. 1Division of Endocrinology, Diabetes and Metabolism and the Diabetes Cardiovascular Center, University of Missouri School of Medicine, Columbia, MO
  2. 2Harry S. Truman Memorial Veterans' Hospital, Columbia, MO
  3. 3Department of Medical Pharmacology and Physiology, University of Missouri School of Medicine, Columbia, MO
  4. 4Department of Internal Medicine, University of Missouri, Columbia, MO
  1. Corresponding author: James R. Sowers, sowersj{at}

By 2030, it is estimated that there will be 439 million people in the world with diabetes. Diabetes is a major risk factor for the development of atherosclerotic peripheral arterial disease (PAD), which is typically caused by progressive narrowing of the arteries in the lower extremities (1). Traditionally, the treatment of PAD has focused on smoking cessation, exercise to promote collateral blood flow, and pharmaceutical vasodilatation to optimize microvascular reserve. Often, aggressive revascularization such as angioplasty and bypass grafting is required to salvage limbs and avoid major amputation in patients with critical limb ischemia. However, restenosis rates after endovascular intervention are high, and while recent advances in drug-eluting balloons and stents have promise, their impact on limb salvage remains unproven (2). Recently, therapeutic angiogenesis has been proposed to induce new blood vessel growth for the treatment or prevention of critical limb ischemia by pharmacological and molecular targeting with vascular endothelial growth factor (VEGF), fibroblastic growth factor, granulocyte colony–stimulating factors, granulocyte-macrophage colony–stimulating factors, angiogenic gene therapy, and endothelial progenitor cells (3). Although preclinical and early-stage clinical results are promising, the strategy of augmenting expression of a single factor has failed to deliver significant clinical improvement. Thus, there remains a clear need for better interventions to induce therapeutic angiogenesis in diabetes-related PAD.

One therapeutic strategy is to increase nitric oxide (NO) in order to stimulate angiogenesis in conditions such as ischemia–reperfusion injury, cerebral ischemia, kidney injury, coronary …

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