title: Role of lipoxygenase metabolites of arachidonic acid in enhanced pulmonary artery contractions of female rabbits.
abstract: Pulmonary arterial hypertension is characterized by elevated pulmonary artery pressure and vascular resistance. In women the incidence is 4-fold greater than that in men. Studies suggest that sustained vasoconstriction is a factor in increased vascular resistance. Possible vasoconstrictor mediators include arachidonic acid-derived lipoxygenase (LO) metabolites. Our studies in rabbits showed enhanced endothelium-dependent contractions to arachidonic acid in pulmonary arteries from females compared with males. Because treatment with a nonspecific LO inhibitor reduced contractions in females but not males, the present study identified which LO isoform contributes to sex-specific pulmonary artery vasoconstriction. The 15- and 5- but not 12-LO protein expressions were greater in females. Basal and A23187-stimulated release of 15-, 5-, and 12-hydroxyeicosatetraenoic acids (HETEs) from females and males were measured by liquid chromatography/mass spectrometry. Only 15-HETE synthesis was greater in females compared with males under both basal and stimulated conditions. Vascular contractions to 15-HETE were enhanced in females compared with males (maximal contraction: 44±6%versus 25±3%). The specific 15-LO inhibitor PD146176 (12 μmol/L) decreased arachidonic acid-induced contractions in females (maximal contraction: 93±4% versus 57±10%). If male pulmonary arteries were incubated with estrogen (1 μmol/L, 18 hours), protein expression of 15-LO and 15-HETE production increased. Mechanisms to explain the increased incidence of pulmonary hypertension in women are not known. Results suggest that the 15-LO pathway is different between females and males and is regulated by estrogen. Understanding this novel sex-specific mechanism may provide insight into the increased incidence of pulmonary hypertension in females.
authors.affiliation: Department of Pharmacology and Toxicology, Medical College of Wisconsin, 8701 Watertown Plank Rd, Milwaukee, WI 53226, USA. spfister@mcw.edu
authors.forename: Sandra L
authors.initials: SL
authors.lastname: Pfister
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D001091:Arachidonate Lipoxygenases / Q000378:metabolism*; D016718:Arachidonic Acid / Q000378:metabolism* / Q000494:pharmacology; D015153:Blotting, Western; D004730:Endothelium, Vascular / Q000187:drug effects / Q000378:metabolism*; D005260:Female; D006893:Hydroxyeicosatetraenoic Acids / Q000378:metabolism* / Q000494:pharmacology; D008297:Male; D013058:Mass Spectrometry; D011651:Pulmonary Artery / Q000187:drug effects / Q000502:physiology*; D011817:Rabbits; D012737:Sex Factors; D014661:Vasoconstriction / Q000187:drug effects / Q000502:physiology*
chemical_list: D006893:Hydroxyeicosatetraenoic Acids; D016718:Arachidonic Acid; D001091:Arachidonate Lipoxygenases