Effect of 5-lipoxygenase on the development of pulmonary hypertension in rats

Am J Physiol Heart Circ Physiol. 2004 May;286(5):H1775-84. doi: 10.1152/ajpheart.00281.2003. Epub 2004 Jan 15.

Abstract

5-Lipoxygenase (5-LO) and its downstream leukotriene products have been implicated in the development of pulmonary hypertension. In this study, we examined the effects of 5-LO overexpression in rat lungs on pulmonary hypertension using a recombinant adenovirus expressing 5-LO (Ad5-LO). Transthoracic echocardiography and right heart catheterization data showed that 5-LO overexpression in the lung did not cause pulmonary hypertension in normal rats; however, it markedly accelerated the progression of pulmonary hypertension in rats treated with monocrotaline (MCT). An increase in pulmonary artery pressure occurred earlier in the rats treated with MCT + Ad5-LO (7-10 days) compared with those treated with control vector, MCT + adenovirus expressing green fluorescent protein (AdGFP), or MCT alone (15-18 days). The weight ratio of the right ventricle to left ventricle plus septum was higher in the MCT + Ad5-LO group than that of the MCT + AdGFP or MCT group (0.45 +/- 0.08 vs. 0.35 +/- 0.03 or 0.33 +/- 0.06). Lung tissue histological sections from MCT + Ad5-LO rats exhibited more severe inflammatory cell infiltration and pulmonary vascular muscularization than those from MCT + AdGFP- or MCT-treated rats. Administration of 5-LO inhibitors, zileuton or MK-886, to either MCT- or MCT + Ad5-LO-treated rats prevented the development of pulmonary hypertension. These data suggest that 5-LO plays a critical role in the progression of pulmonary hypertension in rats and that the detrimental effect of 5-LO is manifest only in the setting of pulmonary vascular endothelial cell dysfunction.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Arachidonate 5-Lipoxygenase / genetics
  • Arachidonate 5-Lipoxygenase / metabolism*
  • Arachidonate 5-Lipoxygenase / pharmacology
  • Drug Synergism
  • Gene Transfer Techniques
  • Heart Septum / pathology
  • Heart Ventricles
  • Hypertension, Pulmonary / chemically induced
  • Hypertension, Pulmonary / etiology*
  • Hypertension, Pulmonary / pathology
  • Lung / drug effects
  • Lung / enzymology*
  • Lung / pathology
  • Male
  • Monocrotaline / pharmacology
  • Myocardium / pathology
  • Organ Size
  • Rats
  • Rats, Sprague-Dawley
  • Time Factors
  • Tissue Distribution

Substances

  • Monocrotaline
  • Arachidonate 5-Lipoxygenase