Nitrite-generated NO circumvents dysregulated arginine/NOS signaling to protect against intimal hyperplasia in Sprague-Dawley rats

J Clin Invest. 2011 Apr;121(4):1646-56. doi: 10.1172/JCI44079. Epub 2011 Mar 23.


Vascular disease, a significant cause of morbidity and mortality in the developed world, results from vascular injury. Following vascular injury, damaged or dysfunctional endothelial cells and activated SMCs engage in vasoproliferative remodeling and the formation of flow-limiting intimal hyperplasia (IH). We hypothesized that vascular injury results in decreased bioavailability of NO secondary to dysregulated arginine-dependent NO generation. Furthermore, we postulated that nitrite-dependent NO generation is augmented as an adaptive response to limit vascular injury/proliferation and can be harnessed for its protective effects. Here we report that sodium nitrite (intraperitoneal, inhaled, or oral) limited the development of IH in a rat model of vascular injury. Additionally, nitrite led to the generation of NO in vessels and SMCs, as well as limited SMC proliferation via p21Waf1/Cip1 signaling. These data demonstrate that IH is associated with increased arginase-1 levels, which leads to decreased NO production and bioavailability. Vascular injury also was associated with increased levels of xanthine oxidoreductase (XOR), a known nitrite reductase. Chronic inhibition of XOR and a diet deficient in nitrate/nitrite each exacerbated vascular injury. Moreover, established IH was reversed by dietary supplementation of nitrite. The vasoprotective effects of nitrite were counteracted by inhibition of XOR. These data illustrate the importance of nitrite-generated NO as an endogenous adaptive response and as a pathway that can be harnessed for therapeutic benefit.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Arginase / metabolism
  • Arginine / physiology*
  • Cell Proliferation / drug effects
  • Cyclin-Dependent Kinase Inhibitor p21 / physiology
  • Hyperplasia / pathology
  • Hyperplasia / physiopathology
  • Hyperplasia / prevention & control
  • Male
  • Myocytes, Smooth Muscle / drug effects
  • Myocytes, Smooth Muscle / pathology
  • Nitric Oxide / biosynthesis
  • Nitric Oxide / physiology*
  • Nitric Oxide Synthase Type III / physiology*
  • Rats
  • Rats, Sprague-Dawley
  • Signal Transduction
  • Sodium Nitrite / administration & dosage*
  • Tunica Intima / drug effects
  • Tunica Intima / injuries
  • Tunica Intima / pathology
  • Tunica Intima / physiology*
  • Xanthine Dehydrogenase / metabolism


  • Cdkn1a protein, rat
  • Cyclin-Dependent Kinase Inhibitor p21
  • Nitric Oxide
  • Arginine
  • Nitric Oxide Synthase Type III
  • Nos3 protein, rat
  • Xanthine Dehydrogenase
  • Arginase
  • arginase I, rat
  • Sodium Nitrite