Inhibition of 5-Lipoxygenase Activating Protein in Hypoxic Rats

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-[1-(4-chlorobenzyl)-3t -butyl-thiot -isopropylindol-2yl ]-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. ( J. Clin. Invest. 1996. 97:2491–2498.)