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Am J Physiol Heart Circ Physiol (January 15, 2004). doi:10.1152/ajpheart.00281.2003
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Submitted on March 31, 2003
Accepted on January 7, 2004

Effect of 5-Lipoxygenase on the Development of Pulmonary Hyperension in Rats

John E. Jones1, Jennifer L. Walker2, Yanli Song2, Norbert Weiss2, Wellington V. Cardoso3, Rubin M. Tuder4, Joseph Loscalzo2, and Ying-Yi Zhang2*

1 Department of Surgery, Boston University School of Medicine, Boston, MA, USA
2 Whitaker Cardiovascular Institute and Evans Department of Medicine, Boston University School of Medicine, Boston, MA, USA
3 The Pulmonary Center, Boston University School of Medicine, Boston, MA, USA
4 Division of Cardiopulmonary Pathology and Critical Care Medicine, Department of Pathology and Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA

* To whom correspondence should be addressed. E-mail: yyzhang{at}bu.edu.

5-Lipoxygenase (5LO) and its downstream leukotriene products have been implicated in the development of pulmonary hypertension. In this study we examined the effects of 5LO overexpression in rat lungs on pulmonary hypertension, using a recombinant adenovirus expressing 5LO (Ad5LO). Transthoracic echocardiography and right heart catheterization data showed that 5LO overexpression in 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+Ad5LO (7-10 days) as compared to those treated with control vector, MCT+AdGFP, or MCT alone (15-18 days). The weight ratio of right ventricle-to-left ventricle plus septum was higher in the MCT+Ad5LO group than that of MCT+AdGFP or MCT alone group (0.45±0.08 vs. 0.35±0.03 or 0.33±0.06). Lung tissue histological sections from MCT+Ad5LO rats exhibited more severe inflammatory cell infiltration and pulmonary vascular muscularization than those from MCT+AdGFP- or MCT-treated rats. Administration of 5LO inhibitors, zileuton or MK-886, to either MCT- or MCT+Ad5LO-treated rats prevented the development of pulmonary hypertension. These data suggest that 5LO plays a critical role in the progression of pulmonary hypertension in rats, and that the detrimental effect of 5LO is manifest only in the setting of pulmonary vascular endothelial cell dysfunction.




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