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Nitrite-generated NO circumvents dysregulated arginine/NOS signaling to protect against intimal hyperplasia in Sprague-Dawley rats
Matthew J. Alef, … , Edith Tzeng, Brian S. Zuckerbraun
Matthew J. Alef, … , Edith Tzeng, Brian S. Zuckerbraun
Published March 23, 2011
Citation Information: J Clin Invest. 2011;121(4):1646-1656. https://doi.org/10.1172/JCI44079.
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Research Article Article has an altmetric score of 2

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

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Abstract

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.

Authors

Matthew J. Alef, Raghuveer Vallabhaneni, Evie Carchman, Sidney M. Morris Jr., Sruti Shiva, Yinna Wang, Eric E. Kelley, Margaret M. Tarpey, Mark T. Gladwin, Edith Tzeng, Brian S. Zuckerbraun

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Figure 6

Arterial injury increased XOR expression and activity.

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Arterial injury increased XOR expression and activity.
(A) XOR immunohis...
(A) XOR immunohistochemistry (red) within uninjured control vessels and injured vessels. Scale bar: 50 μm. (B) Western blot analysis demonstrated increased XOR within injured versus uninjured vessels (representative results of 4 independent experiments). (C) XOR activity is increased within injured versus uninjured control vessels (*P < 0.05; n = 7–8 vessels per group). (D) A NOx– diet resulted in significantly greater I/M ratios compared with rats kept on regular chow (n = 6/group, *P < 0.01). (E) A tungsten-rich diet, which inhibits XOR activity, resulted in significantly increased I/M compared with standard chow (n = 6/group, *P < 0.01).

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ISSN: 0021-9738 (print), 1558-8238 (online)

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