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.

Effect of human 15-lipoxygenase-1 metabolites on vascular function in mouse mesenteric arteries and hearts

“…Initially, EETs, H 2 O 2 and C-type natriuretic peptide were described to function as EDHFs 24–26 in mice. As we recently demonstrated, LO metabolites of AA also mediate EDHF activity in murine resistance arteries 13, 22 . The EDHF activity in these arteries is inhibited by LO and hydroperoxide isomerase inhibitors.…”

“…While 15-LO-1 plays an important role in endothelium-dependent relaxation in rabbit arteries 2 , the LO that contributes to vascular relaxations in the mouse has not been identified. In a recent study 13 we found no aortic expression of Alox15, the mouse homologue of rabbit and human 15-LO-1 11, 14, 15 . As a consequence, there was no difference between vascular relaxations to ACh in aortas from wild type (WT) and Alox15 knockout mice.…”

Cytosolic Phospholipase A 2 α Is Critical for Angiotensin II–Induced Hypertension and Associated Cardiovascular Pathophysiology

“…53 Also mice lacking macrophage 12/15 LO have been shown to be resistant to L-NAME or deoxycorticosterone-salt induced hypertension. 54 Ang II is known to cause hypertension by increasing oxidative stress in subfornical organ (SFO) of circumventricular organs and via its projections to paraventricular nucleus and from there to the brain stem, finally resulting in increased sympathetic activity. 55 cPLA 2 α is also present in the brain 13,16 and intracerebroventricular administration of PGE2 increases sympathetic nervous activity, vasopressin release and BP.…”

Mammalian lipoxygenases and their biological relevance

“…Interestingly, chronic hypoxia and hypercholesterolemia enhanced ALOX15 mediated vasorelaxation in rabbit arteries [223, 224]. More direct evidence for the in vivo relevance of ALOX15 in blood pressure regulation was recently provided by experiments with ALOX15-deficient mice [225]. Although systolic blood pressures did not differ between these mice and wild-type controls Alox15 −/− -mice exhibited higher resistance towards L-NAME- and high-salt-induced hypertension than corresponding controls.…”

“…Interestingly, injection of wild-type peritoneal macrophages, which are a major source of ALOX15 in mice, into ALOX15-deficient animals abolished their resistance toward L-NAME-induced hypertension. Inversely, wildtype mice acquired resistance to L-NAME-induced hypertension after depletion of macrophages by clodronate injection [225]. …”