Role of arachidonic acid lipoxygenase metabolites in the regulation of vascular tone - PubMed (original) (raw)

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Role of arachidonic acid lipoxygenase metabolites in the regulation of vascular tone

Yuttana Chawengsub et al. Am J Physiol Heart Circ Physiol. 2009 Aug.

Abstract

Stimulation of vascular endothelial cells with agonists such as acetylcholine (ACh) or bradykinin or with shear stress activates phospholipases and releases arachidonic acid (AA). AA is metabolized by cyclooxygenases, cytochrome P-450s, and lipoxygenases (LOs) to vasoactive products. In some arteries, a substantial component of the vasodilator response is dependent on LO metabolites of AA. Nitric oxide (NO)- and prostaglandin (PG)-independent vasodilatory responses to ACh and AA are reduced by inhibitors of LO and by antisense oligonucleotides specifically against 15-LO-1. Vasoactive 15-LO metabolites derived from the vascular endothelium include 15-hydroxy-11,12-epoxyeicosatrienoic acid (15-H-11,12-HEETA) that is hydrolyzed by soluble epoxide hydrolase to 11,12,15-trihydroxyeicosatrienoic acid (11,12,15-THETA). HEETA and THETA are endothelium-derived hyperpolarizing factors that induce vascular relaxations by activation of smooth muscle apamin-sensitive, calcium-activated, small-conductance K(+) channels causing hyperpolarization. In other arteries, the 12-LO metabolite 12-hydroxyeicosatetraenoic acid is synthesized by the vascular endothelium and relaxes smooth muscle by large-conductance, calcium-activated K(+) channel activation. Thus formation of vasodilator eicosanoids derived from LO pathways contributes to the regulation of vascular tone, local blood flow, and blood pressure.

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Figures

Fig. 1.

Fig. 1.

Schematic of the role of Ca2+ on relaxing factor production in vascular endothelial cells. Activation of muscarinic receptors leads to the production of inositol 1,4,5-trisphosphate (IP3), which releases Ca2+ from the endoplasmic reticulum (ER). Extracellular Ca2+ can enter the endothelial cell through nonselective Ca2+-permeable cation channels or store-operated Ca2+ channels, which are regulated by the ER Ca2+ store. An increase in Ca2+ concentration promotes K+ efflux through activated Ca2+-dependent K+ (KCa) channels, causing membrane hyperpolarization, which in turn increases Ca2+ influx. Intracellular Ca2+ binds to calmodulin (CaM) and activates nitric oxide synthase (NOS) and the production of nitric oxide (NO) or stimulates phospholipase A2 (PLA2), which results in the release of arachidonic acid (AA) from the cell plasma membrane. Free AA also can be obtained from the phospholipase C (PLC) pathway, in which diacylglycerol (DAG) is hydrolyzed at the sn-1 position by DAG lipase to monoacylglycerol (MAG), specifically 2-arachidonylglycerol (2-AG). MAG lipase or fatty acid amidohydrolase (FAAH) releases free AA from 2-AG. Free AA can be metabolized through cyclooxygenase (COX), cytochrome _P_-450 (CYP), and/or lipoxygenase (LO) pathways to produce relaxing factors. PGI2, prostacyclin; EET, epoxyeicosatrienoic acid; HEETA, hydroxyepoxyeicosatrienoic acid; THETA, trihydroxyeicosatrienoic acid; HETE, hydroxyeicosatetraenoic acid; BKCa, large-conductance KCa channel; SKCa, apamin-sensitive KCa channel; Kir, inward rectifying K+ channel; AC, adenylyl cyclase; sGC, soluble guanylate cyclase.

Fig. 2.

Fig. 2.

Metabolism of [14C]AA by rabbit aorta, mouse aorta, dog mesenteric arteries, and guinea pig carotid arteries. Arterial rings with an intact endothelium were incubated with indomethacin and [14C]AA. Metabolites were extracted and resolved by reverse-phase HPLC (21). Migration times of known standards are indicated by arrows above the chromatogram. CPM, counts per minute.

Fig. 3.

Fig. 3.

Proposed biosynthesis pathway of HEETAs and THETAs. AA is converted to 15(S)-hydroperoxyeicosatetraenoic acid [15(S)-HPETE] by 15-LO-1. 15(S)-HPETE is converted by hydroperoxide isomerases to the HEETAs. 15-Hydroxy-11,12-epoxyeicosatrienoic acid (15-H-11,12-EETA) can be hydrolyzed by either soluble epoxide hydrolase (sEH) or acid to THETAs. It is hydrolyzed to 11,12,15-THETA by sEH. However, with acid hydrolysis, 15-H-11,12-EETA is hydrolyzed to both 11,12,15- and 11,14,15-THETA. The exact stereochemistry of 15-H-11,12-EETAs is not known.

Fig. 4.

Fig. 4.

Endothelium-derived hyperpolarizing factor (EDHF)-mediated responses to acetylcholine (ACh) involve 2 mechanisms acting in parallel. ACh activates intermediate-conductance KCa (IKCa) channels on endothelial cells (EC), releasing K+ that activates Kir channels on smooth muscle. ACh also releases AA in endothelial cells that is metabolized by 15-LO to 15-H-11,12-EETA and 11,12,15-THETA. THETA activates SKCa channels on smooth muscle. These 2 pathways cause smooth muscle cell membrane hyperpolarization and relaxation. Inhibitors of these enzymes and channels are indicated. PL, phospholipase; CDC, cinnamyl-3,4-dihydroxy-α-cyanocinnamate; ETYA, 5,8,11,14-eicosatetraynoic acid; NDGA, nordihydroguaiaretic acid; ChTX, charybdotoxin; SMC, smooth muscle cells.

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References

    1. Aggarwal N, Gauthier KM, Campbell WB. 15-Lipoxygenase metabolites contribute to age-related reductions in acetylcholine-induced hypotension in rabbits. Am J Physiol Heart Circ Physiol 295: H89–H96, 2008. - PMC - PubMed
    1. Aggarwal N, Pfister SL, Campbell WB. Hypercholesterolemia enhances 15-lipoxygenase mediated vasorelaxation and acetylcholine-induced hypotension. Arterioscler Thromb Vasc Biol 28: 2209–2215, 2008. - PubMed
    1. Aggarwal NT, Chawengsub Y, Gauthier KM, Viita H, Yla-Herttuala S, Campbell WB. Endothelial 15-lipoxygenase-1 overexpression increases acetylcholine-induced hypotension and vasorelaxation in rabbits. Hypertension 51: 246–251, 2008. - PubMed
    1. Aggarwal NT, Holmes BB, Cui L, Viita H, Yla-Herttuala S, Campbell WB. Adenoviral expression of 15-lipoxygenase-1 in rabbit aortic endothelium: role in arachidonic acid-induced relaxation. Am J Physiol Heart Circ Physiol 292: H1033–H1041, 2007. - PubMed
    1. Anning PB, Coles B, Bermudez-Fajardo A, Martin PWM, Levison BS, Hazen SL, Funk CD, Kuhn H, O'Donnell VB. Elevated endothelial nitric oxide bioactivity and resistance to angiotensin-dependent hypertension in 12/15-lipoxygenase knockout mice. Am J Pathol: 653–662, 2005. - PMC - PubMed

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