Inducible endothelium-derived hyperpolarizing factor: role of the 15-lipoxygenase-EDHF pathway - PubMed (original) (raw)

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Inducible endothelium-derived hyperpolarizing factor: role of the 15-lipoxygenase-EDHF pathway

William B Campbell et al. J Cardiovasc Pharmacol. 2013 Mar.

Abstract

Endothelium-derived hyperpolarizing factors (EDHFs) regulate vascular tone by contributing to the vasorelaxations to shear stress and endothelial agonists such as bradykinin and acetylcholine. 15(S)-Hydroxy-11,12-epoxyeicosatrienoic acid (15-H-11,12-EETA) and 11(R),12(S),15(S)-trihydroxyeicosatrienoic acid (11,12,15-THETA) are endothelial metabolites of the 15-lipoxygenase (15-LO) pathway of arachidonic acid metabolism and are EDHFs. 11,12,15-THETA activates small conductance, calcium-activated potassium channels on smooth muscle cells causing membrane hyperpolarization, and relaxation. Expression levels of 15-LO in the endothelium regulate the activity of the 15-LO/15-H-11,12-EETA/11,12,15-THETA pathway and its contribution to vascular tone. Regulation of its expression is by transcriptional, translational, and epigenetic mechanisms. Hypoxia, hypercholesterolemia, atherosclerosis, anemia, estrogen, interleukins, and possibly other hormones increase 15-LO expression. An increase in 15-LO results in increased synthesis of 15-H-11,12-EETA and 11,12,15-THETA, increased membrane hyperpolarization, and enhanced contribution to relaxation by endothelial agonists. Thus, the 15-LO pathway represents the first example of an inducible EDHF. In addition to 15-LO metabolites, a number of chemicals have been identified as EDHFs and their contributions to vascular tone vary with species and vascular bed. The reason for multiple EDHFs has evaded explanation. However, EDHF functioning as constitutive EDHFs or inducible EDHFs may explain the need for chemically and biochemically distinct pathways for EDHF activity and the variation in EDHFs between species and vascular beds. This new EDHF classification provides a framework for understanding EDHF activity in physiological and pathological conditions.

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Figures

Figure 1

Figure 1

Signaling mechanisms of the five major endothelium-derived hyperpolarizing factors (EDHFs). Shear stress or endothelium-dependent agonists including acetylcholine and bradykinin stimulate EDHF-dependent vascular relaxation. EDHF mediators include: (1) electrical transmission of endothelial hyperpolarization through myoendothelial gap junctions, (1) K ion, (2) C-type natriuretic peptide (CNP), (3) hydrogen peroxide (H2O2), (4) epoxyeicosatrienoic acids (EETs) and (5) 15-lipoxygenase-1 (15-LO-1) metabolites, 15-H-11,12-EETA and 11,12,15-THETA. The 15-LO-1 inducible EDHF pathway is highlighted. The shaded numbers in the figure refer to the Classification of EDHF section of the text and correspond to numbered descriptions of 5 major EDHFs.

Figure 2

Figure 2

15-Lipoxygenase-1 pathway of endothelial cell arachidonic acid (AA) metabolism. 15(S)-hydroperoxyeicosatetraenoic acid (15(S)-HPETE), 15-hydroxy-11,12-epoxyeicosatrienoic acid (15-H-11,12-EETA), 15(S)-hydroxyeicosatetraenoic acid (15(S)-HETE), 11,12,15-trihydroxyeicosatrienoic acid (11,12,15-THETA). * 15-H-11,12-EETA and 11,12,15-THETA cause vascular relaxation and function as EDHFs.

Figure 3

Figure 3

Effect of hypoxia on 15-LO activity in the rabbit vasculature. (A) AA metabolism of rabbit aortic endothelial cells exposed to normal oxygen (21% O2, normoxia) or reduced oxygen (0.7% O2, hypoxia). Endothelial cells were incubated with 14C-AA in the presence of indomethacin (10 μM) for 8 h under normoxic or hypoxic conditions. The media was removed, extracted and metabolites resolved by reverse-phase HPLC. Radioactivity of column fractions was measured by scintillation counting. Migration times of known standards are noted on each chromatogram. (B) AA-induced hyperpolarization responses in mesenteric arteries from normoxic or hypoxic rabbits. Male 8 week old rabbits were exposed to either normoxic conditions (21% O2) or hypoxic conditions (12% O2) for 5 days. Membrane potential cell impalement recordings were made in the freshly dissected arterial segments incubated with indomethacin (10 μM) and phenylephrine (100 nM) with or without AA (10 μM). (C) Acetylcholine relaxations of mesenteric arteries from normoxic (top trace) or hypoxic (bottom trace) rabbits. Arterial rings were mounted in a myograph, stretched to a basal tension of 1 gram, treated with indomethacin (10 μM) and N-nitro-L-arginine (30 μM) and constricted with phenylephrine (0.1 – 1.0 μM). Increasing concentrations of acetylcholine were added and relaxation responses recorded.

Figure 4

Figure 4

Effect of a high cholesterol diet on aortic vascular activity. Male 8 week old rabbits were fed either normal chow (normal) or cholesterol enriched (2% cholesterol) chow (cholesterol) for 2 weeks. (A) AA-induced hyperpolarization responses. Membrane potential cell impalement recordings were made in the freshly dissected aortic segments incubated with indomethacin (10 μM) and phenylephrine (100 nM) with or without AA (10 μM). (B) Acetylcholine relaxations. Arterial rings from rabbits fed normal chow (top trace) or rabbits fed cholesterol-enriched chow (bottom trace) were mounted in a myograph, stretched to a basal tension of 2 grams, treated with indomethacin (10 μM) and N-nitro-L-arginine (30 μM) and constricted with phenylephrine (0.1 – 1.0 μM). Increasing concentrations of acetylcholine were added and relaxation responses recorded.

Figure 5

Figure 5

Co-release of constitutive (c) and inducible (i) EDHFs mediate synergistic vasorelaxation. In vascular endothelial cells, acetylcholine activates; 1) calcium influx which stimulates IKCa and SKCa channels resulting in K ion efflux (the cEDHF pathway) and 2) PLA2 release of AA from membrane phospholipids. AA is metabolized by 15-LO-1 to HEETA and THETA (the iEDHF pathway). 15-LO-1 expression is increased by hypoxia, hypercholesterolemia, interleukin-4 (IL-4), interleukin-13 (IL-13), estrogen and anemia. The cEDHF and iEDHF pathways cause smooth muscle hyperpolarization via distinct synergistic mechanisms. For the cEDHF pathway, endothelial cell hyperpolarization from K ion efflux is transmitted to the smooth muscle through myoendothelial gap junctions or K ions activate smooth muscle KIR channels and the Na/K ATPase. HEETAs and THEETAs from the iEDHF pathway activate smooth muscle SKCa channels.

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