title: Mice lacking macrophage 12/15-lipoxygenase are resistant to experimental hypertension.
abstract: In mouse arteries, Alox15 [leukocyte-type 12/15-lipoxygenase (LO)] is assumed to regulate vascular function by metabolizing arachidonic acid (AA) to dilator eicosanoids that mediate the endothelium-dependent relaxations to AA and acetylcholine (ACh). We used Alox15(-/-) mice, made by targeted disruption of the Alox15 gene, to characterize its role in the regulation of blood pressure and vascular tone. Systolic blood pressures did not differ between wild-type (WT) and Alox15(-/-) mice between 8-12 wk of age, but Alox15(-/-) mice exhibited resistance toward both N(G)-nitro-L-arginine-methyl ester (L-NAME)- and deoxycorticosterone acetate (DOCA)/high-salt-induced hypertension. ACh relaxed mesenteric arteries and abdominal aortas of WT and Alox15(-/-) mice to an identical extent. The LO inhibitor nordihydroguaiaretic acid attenuated the ACh relaxations by 35% in arteries from both WT and Alox15(-/-) mice. Reverse-phase HPLC analysis of [(14)C]AA metabolites in aorta and peritoneal macrophages (PM) revealed differences. Unlike PM, aorta tissue did not produce detectable amounts of 15-hydroxyeicosatetraenoic acid. Although Alox15 mRNA was detected in aorta, high-resolution gel electrophoresis with immunodetection revealed no Alox15 protein expression. Unlike aorta, Alox15 protein was detected in PM, intestine, fat, lung, spleen, and skin from WT, but not Alox15(-/-), mice. Injection of WT PM, a primary source of Alox15 protein, into Alox15(-/-) mice abolished their resistance toward L-NAME-induced hypertension. On the other hand, WT mice acquired resistance to L-NAME-induced hypertension after depletion of macrophages by clodronate injection. These studies indicate that Alox15 is involved in development of experimental hypertension by altering macrophage functions but not via synthesis of the vasoactive LO metabolites in mouse arteries.
authors.affiliation: Department of Pharmacology and Toxicology, Medical College of Wisconsin, Milwaukee, 53226, USA. tkriska@mcw.edu
authors.forename: Tamas
authors.initials: T
authors.lastname: Kriska
authors.forename: Cody
authors.initials: C
authors.lastname: Cepura
authors.forename: Devora
authors.initials: D
authors.lastname: Magier
authors.forename: Lawan
authors.initials: L
authors.lastname: Siangjong
authors.forename: Kathryn M
authors.initials: KM
authors.lastname: Gauthier
authors.forename: William B
authors.initials: WB
authors.lastname: Campbell
mesh_terms: D000818:Animals; D001092:Arachidonate 12-Lipoxygenase / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism; D001093:Arachidonate 15-Lipoxygenase / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism; D001794:Blood Pressure / Q000502:physiology; D003900:Desoxycorticosterone / Q000009:adverse effects / Q000031:analogs & derivatives; D004195:Disease Models, Animal; D006973:Hypertension / Q000139:chemically induced / Q000503:physiopathology* / Q000517:prevention & control*; D008264:Macrophages / Q000201:enzymology* / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009131:Muscle, Smooth, Vascular / Q000378:metabolism; D019331:NG-Nitroarginine Methyl Ester / Q000009:adverse effects; D014664:Vasodilation / Q000502:physiology
chemical_list: D003900:Desoxycorticosterone; C521960:Alox15 protein, mouse; D001092:Arachidonate 12-Lipoxygenase; D001093:Arachidonate 15-Lipoxygenase; D019331:NG-Nitroarginine Methyl Ester