title: Inhibition of 5-lipoxygenase-activating protein (FLAP) reduces pulmonary vascular reactivity and pulmonary hypertension in hypoxic rats.
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.
authors.affiliation: Pulmonary Hypertension Center, Department of Pathology, University of Colorado Health Sciences Center, Denver 80262, USA.
authors.forename: N F
authors.initials: NF
authors.lastname: Voelkel
authors.forename: R M
authors.initials: RM
authors.lastname: Tuder
authors.forename: K
authors.initials: K
authors.lastname: Wade
authors.forename: M
authors.initials: M
authors.lastname: Höper
authors.forename: R A
authors.initials: RA
authors.lastname: Lepley
authors.forename: J L
authors.initials: JL
authors.lastname: Goulet
authors.forename: B H
authors.initials: BH
authors.lastname: Koller
authors.forename: F
authors.initials: F
authors.lastname: Fitzpatrick
mesh_terms: D058927:5-Lipoxygenase-Activating Proteins; D000531:Altitude; D000804:Angiotensin II / Q000494:pharmacology; D000818:Animals; D001094:Arachidonate 5-Lipoxygenase / Q000032:analysis / Q000096:biosynthesis / Q000378:metabolism*; D006332:Cardiomegaly / Q000517:prevention & control; D002352:Carrier Proteins / Q000032:analysis / Q000037:antagonists & inhibitors / Q000378:metabolism*; D004730:Endothelium, Vascular / Q000201:enzymology / Q000473:pathology / Q000503:physiopathology*; D015870:Gene Expression; D006976:Hypertension, Pulmonary / Q000503:physiopathology* / Q000517:prevention & control; D000860:Hypoxia; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D007211:Indoles / Q000494:pharmacology*; D007249:Inflammation; D016859:Lipoxygenase Inhibitors / Q000494:pharmacology*; D008297:Male; D008565:Membrane Proteins / Q000032:analysis / Q000037:antagonists & inhibitors / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D011651:Pulmonary Artery / Q000503:physiopathology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D014661:Vasoconstriction / Q000187:drug effects; D002722:Chlorobenzenes
chemical_list: D058927:5-Lipoxygenase-Activating Proteins; D000804:Angiotensin II; D001094:Arachidonate 5-Lipoxygenase; D002352:Carrier Proteins; D007211:Indoles; D016859:Lipoxygenase Inhibitors; D008565:Membrane Proteins; C548593:Alox5ap protein, mouse; C548594:Alox5ap protein, rat; C060893:MK-886; D002722:Chlorobenzenes