Nitrite potently inhibits hypoxic and inflammatory pulmonary arterial hypertension and smooth muscle proliferation via xanthine oxidoreductase-dependent nitric oxide generation. Academic Article uri icon

Overview

MeSH

  • Administration, Inhalation
  • Animals
  • Cell Division
  • Cells, Cultured
  • Chronic Disease
  • Cyclin-Dependent Kinase Inhibitor p21
  • Disease Models, Animal
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Monocrotaline
  • Myocytes, Smooth Muscle
  • Pulmonary Artery
  • Rats
  • Rats, Sprague-Dawley

MeSH Major

  • Hypertension, Pulmonary
  • Hypoxia
  • Nitric Oxide
  • Sodium Nitrite
  • Xanthine Dehydrogenase

abstract

  • Pulmonary arterial hypertension is a progressive proliferative vasculopathy of the small pulmonary arteries that is characterized by a primary failure of the endothelial nitric oxide and prostacyclin vasodilator pathways, coupled with dysregulated cellular proliferation. We have recently discovered that the endogenous anion salt nitrite is converted to nitric oxide in the setting of physiological and pathological hypoxia. Considering the fact that nitric oxide exhibits vasoprotective properties, we examined the effects of nitrite on experimental pulmonary arterial hypertension. We exposed mice and rats with hypoxia or monocrotaline-induced pulmonary arterial hypertension to low doses of nebulized nitrite (1.5 mg/min) 1 or 3 times a week. This dose minimally increased plasma and lung nitrite levels yet completely prevented or reversed pulmonary arterial hypertension and pathological right ventricular hypertrophy and failure. In vitro and in vivo studies revealed that nitrite in the lung was metabolized directly to nitric oxide in a process significantly enhanced under hypoxia and found to be dependent on the enzymatic action of xanthine oxidoreductase. Additionally, physiological levels of nitrite inhibited hypoxia-induced proliferation of cultured pulmonary artery smooth muscle cells via the nitric oxide-dependent induction of the cyclin-dependent kinase inhibitor p21(Waf1/Cip1). The therapeutic effect of nitrite on hypoxia-induced pulmonary hypertension was significantly reduced in the p21-knockout mouse; however, nitrite still reduced pressures and right ventricular pathological remodeling, indicating the existence of p21-independent effects as well. These studies reveal a potent effect of inhaled nitrite that limits pathological pulmonary arterial hypertrophy and cellular proliferation in the setting of experimental pulmonary arterial hypertension.

publication date

  • January 5, 2010

has subject area

  • Administration, Inhalation
  • Animals
  • Cell Division
  • Cells, Cultured
  • Chronic Disease
  • Cyclin-Dependent Kinase Inhibitor p21
  • Disease Models, Animal
  • Hypertension, Pulmonary
  • Hypoxia
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Monocrotaline
  • Myocytes, Smooth Muscle
  • Nitric Oxide
  • Pulmonary Artery
  • Rats
  • Rats, Sprague-Dawley
  • Sodium Nitrite
  • Xanthine Dehydrogenase

Research

keywords

  • Journal Article

Identity

Language

  • eng

Digital Object Identifier (DOI)

  • 10.1161/CIRCULATIONAHA.109.891077

PubMed ID

  • 20026772

Additional Document Info

start page

  • 98

end page

  • 109

volume

  • 121

number

  • 1