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Research Article Free access | 10.1172/JCI118696

Inhibition of 5-lipoxygenase-activating protein (FLAP) reduces pulmonary vascular reactivity and pulmonary hypertension in hypoxic rats.

N F Voelkel, R M Tuder, K Wade, M Höper, R A Lepley, J L Goulet, B H Koller, and F Fitzpatrick

Pulmonary Hypertension Center, Department of Pathology, University of Colorado Health Sciences Center, Denver 80262, USA.

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Pulmonary Hypertension Center, Department of Pathology, University of Colorado Health Sciences Center, Denver 80262, USA.

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Pulmonary Hypertension Center, Department of Pathology, University of Colorado Health Sciences Center, Denver 80262, USA.

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Pulmonary Hypertension Center, Department of Pathology, University of Colorado Health Sciences Center, Denver 80262, USA.

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Pulmonary Hypertension Center, Department of Pathology, University of Colorado Health Sciences Center, Denver 80262, USA.

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Pulmonary Hypertension Center, Department of Pathology, University of Colorado Health Sciences Center, Denver 80262, USA.

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Pulmonary Hypertension Center, Department of Pathology, University of Colorado Health Sciences Center, Denver 80262, USA.

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Pulmonary Hypertension Center, Department of Pathology, University of Colorado Health Sciences Center, Denver 80262, USA.

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Published June 1, 1996 - More info

Published in Volume 97, Issue 11 on June 1, 1996
J Clin Invest. 1996;97(11):2491–2498. https://doi.org/10.1172/JCI118696.
© 1996 The American Society for Clinical Investigation
Published June 1, 1996 - Version history
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Abstract

Chronically elevated shear stress and inflammation are important in hypertensive lung vessel remodeling. We postulate that 5-lipoxygenase (5-LO) is a molecular determinant of these processes. Immunohistology localized the 5-LO to macrophages of normal and chronically hypoxic rat lungs and also to vascular endothelial cells in chronically hypoxic lungs only. In situ hybridization of normal and chronically hypoxic lungs demonstrated that 5-LO mRNA is expressed in macrophages. Rats hypoxic for 4 wk-developed pulmonary hypertension increased translocation of the lung 5-LO from the cytosol to the membrane fraction and increased levels of lung tissue 5-lipoxygenase-activating protein (FLAP). A FLAP ligand, 3-[l-(4-chlorobenzyl)-3-t-butyl-thio-t-isopropylindol-2-yl]-2,2- dimethylpropanoic acid (MK-886), inhibited the acute angiotensin II and hypoxia-induced pulmonary vasoconstriction in vitro and the development of chronic hypoxic pulmonary hypertension in rats in vivo. Mice bred with the deletion of the 5-LO enzyme (5-LO knockout) developed less right heart hypertrophy than age-matched 5-LO competent mice. Our results support the hypothesis that the 5-LO is involved in lung vascular tone regulation and in the development of chronic pulmonary hypertension in hypoxic rodent models.

Version history
  • Version 1 (June 1, 1996): No description
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