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Targeted disruption of the Alox15 gene makes mice resistant to angiotensin II-, DOCA/salt-, and Nω-nitro-L-arginine methyl ester (L-NAME)-induced experimental hypertension. Macrophages, a primary source of Alox15, are facilitating this resistance, but the underlying mechanism is not known. Because Alox15 metabolites are peroxisome proliferator-activated receptor (PPAR)Υ agonists, we hypothesized that activation of macrophage PPARΥ is the key step in Alox15 mediation of hypertension. Thioglycollate, used for macrophage elicitation, selectively upregulated PPARΥ and its target gene CD36 in peritoneal macrophages of both wild-type (WT) and Alox15-/- mice. Moreover, thioglycollate-injected Alox15 mice became hypertensive upon L-NAME treatment. A similar hypertensive effect was observed with adoptive transfer of thioglycollate-elicited Alox15-/- macrophages into Alox15-/- recipient mice. The role of PPAR was further specified by using the selective PPARΥ antagonist GW9662.WT mice treated with 50 µ/kg daily dose of GW9662 for 12 days became resistant to L-NAME-induced hypertension. The PPARΥ antagonist treatment also prevented L-NAME-induced hypertension in thioglycollate-injected Alox15-/- mice, indicating a PPARΥ-mediated effect in macrophage elicitation and the resultant hypertension. These results indicate a regulatory role for macrophage-localized PPARΥ in L-NAME-induced experimental hypertension. [ABSTRACT FROM AUTHOR]

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 NG-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 [14C]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. [ABSTRACT FROM AUTHOR]