Effect of 5-lipoxygenase on the development of pulmonary hypertension in rats.
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.
Jones
John E
JE
Department of Surgery, Boston University School of Medicine, Boston, MA 02118, USA.
Walker
Jennifer L
JL
Song
Yanli
Y
Weiss
Norbert
N
Cardoso
Wellington V
WV
Tuder
Rubin M
RM
Loscalzo
Joseph
J
Zhang
Ying-Yi
YY
D000818:Animals; D001094:Arachidonate 5-Lipoxygenase / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D004357:Drug Synergism; D018014:Gene Transfer Techniques; D006346:Heart Septum / Q000473:pathology; D006352:Heart Ventricles; D006976:Hypertension, Pulmonary / Q000139:chemically induced / Q000209:etiology* / Q000473:pathology; D008168:Lung / Q000187:drug effects / Q000201:enzymology* / Q000473:pathology; D008297:Male; D016686:Monocrotaline / Q000494:pharmacology; D009206:Myocardium / Q000473:pathology; D009929:Organ Size; D051381:Rats; D017207:Rats, Sprague-Dawley; D013997:Time Factors; D014018:Tissue Distribution
D016686:Monocrotaline; D001094:Arachidonate 5-Lipoxygenase