Metabolism of adrenic acid to vasodilatory 1α,1β-dihomo-epoxyeicosatrienoic acids by bovine coronary arteries

Yi, Xiu-Yu; Gauthier, Kathryn M.; Cui, Lijie; Nithipatikom, Kasem; Falck, John R.; Campbell, William B.

doi:10.1152/ajpheart.00947.2006

Cited by 30 publications

(45 citation statements)

References 24 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…For LC/MS, column eluates were collected as four major peaks corresponding to the reported major adrenic acid metabolites (10). The retention time range of the four peaks are: 3–6.8 min, 15.6–20.6 min, 21–24.6 min and 24.6–30 min.…”

Section: Methodsmentioning

confidence: 99%

“…Our laboratory has demonstrated that adrenic acid is metabolized in human vascular endothelial cells to DH-prostacyclin (PGI 2 ), which inhibited thrombin-induced platelet aggregation (9). We have also demonstrated that adrenic acid induces concentration-dependent relaxations of bovine coronary arteries, which were endothelium-dependent, blocked by K + channel inhibition, and inhibited by COX and CYP450 inhibition (10). Several adrenic acid metabolites of coronary arteries were isolated and identified, including DH-PGs and DH-epoxyeicosatrienoic acids (EETs).…”

Section: Introductionmentioning

confidence: 91%

“…Several adrenic acid metabolites of coronary arteries were isolated and identified, including DH-PGs and DH-epoxyeicosatrienoic acids (EETs). In particular, DH-16,17-EET, the dihomo analog of 14,15-EET, induced concentration-dependent relaxations by activation of vascular smooth muscle K + channels and hyperpolarization (10). These observations are consistent with another study examining the effect of DH-EETs in porcine coronary arteries (11).…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Adrenic Acid Metabolites as Endogenous Endothelium-Derived and Zona Glomerulosa-Derived Hyperpolarizing Factors

et al. 2010

Self Cite

View full text Add to dashboard Cite

Abstract-Adrenic acid (docosatetraenoic acid), an abundant fatty acid in the adrenal gland, is identical to arachidonic acid except for 2 additional carbons on the carboxyl end. Adrenic acid is metabolized by cyclooxygenases, cytochrome P450s, and lipoxygenases; however, little is known regarding the role of adrenic acid and its metabolites in vascular tone. Because of its abundance in the adrenal gland, we investigated the role of adrenic acid in vascular tone of bovine adrenal cortical arteries and its metabolism by bovine adrenal zona glomerulosa cells. In adrenal cortical arteries, adrenic acid caused concentrationdependent relaxations, which were inhibited by the epoxyeicosatrienoic acid antagonist 14,15-epoxyeicosa-5(Z)-enoic acid and the cytochrome P450 inhibitor SKF-525A. The large-conductance calcium-activated potassium channel blocker iberiotoxin or removal of the endothelium abolished these relaxations. Reverse-phase high-pressure liquid chromatography and liquid chromatography/mass spectrometry isolated and identified numerous adrenic acid metabolites from zona glomerulosa cells, including dihomo-epoxyeicosatrienoic acids and dihomo-prostaglandins. In denuded adrenal cortical arteries, adrenic acid caused concentration-dependent relaxations in the presence of zona glomerulosa cells but not in their absence. These relaxations were inhibited by SKF-525A, 14,15-epoxyeicosa-5(Z)-enoic acid, and iberiotoxin. Dihomo-16,17-epoxyeicosatrienoic acid caused concentration-dependent relaxations of adrenal cortical arteries, which were inhibited by 14,15-epoxyeicosa-5(Z)-enoic acid and high potassium. Our results suggest that adrenic acid relaxations of bovine adrenal cortical arteries are mediated by endothelial and zona glomerulosa cell cytochrome P450 metabolites. Thus, adrenic acid metabolites could function as endogenous endothelium-derived and zona glomerulosa-derived hyperpolarizing factors in the adrenal cortex and contribute to the regulation of adrenal blood flow. Key Words: adrenal cortex Ⅲ cyclooxygenase Ⅲ cytochrome P450 Ⅲ endothelium-dependent relaxation Ⅲ endothelium-derived hyperpolarizing factor Ⅲ epoxygenase Ⅲ potassium channels A rachidonic acid (20:4; -6) is the precursor to eicosanoids, a group of signaling molecules with diverse physiological action, including the regulation of vascular tone. Adrenic acid (7,10,13,16-docosatetraenoic acid, 22:4; -6) is an abundant polyunsaturated fatty acid in the adrenal gland, brain, kidney, and vasculature that is identical to arachidonic acid except for 2 additional carbons on the carboxyl end. 1-5 Adrenic acid is formed by arachidonic acid chain elongation or elongation and desaturation of the essential fatty acid linoleic acid (18:2; -6), the precursor to arachidonic acid. 1,6 Adrenic acid can also be converted to arachidonic acid by ␤-oxidation. 1,3,6,7 As with arachidonic acid, adrenic acid is metabolized by cyclooxygenases (COX), lipoxygenases (LO), and cytochrome P450s (CYP450s) to dihomo (DH) eicosanoids. Adrenic acid is metabolized in the renal m...

show abstract

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 91%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Adrenic Acid Metabolites as Endogenous Endothelium-Derived and Zona Glomerulosa-Derived Hyperpolarizing Factors

et al. 2010

Self Cite

View full text Add to dashboard Cite

show abstract

“…11,12- and 14–15-EET undergo partial β-oxidation to a 16-carbon metabolites and chain-elongation to a 22-carbon metabolites that have bioactivity [22,84,85]. Likewise, 11,12-DHET undergoes partial β-oxidation to a 16-carbon metabolite in porcine aortic smooth muscle cells [9].…”

Section: Metabolism Of Pufa Epoxidesmentioning

confidence: 99%

Cytochrome P450 epoxygenase pathway of polyunsaturated fatty acid metabolism

Spector

Kim

2015

Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biolog

204

172

View full text Add to dashboard Cite

Polyunsaturated fatty acids (PUFA) are oxidized by cytochrome P450 epoxygenases to PUFA epoxides which function as potent lipid mediators. The major metabolic pathways of PUFA epoxides are incorporation into phospholipids and hydrolysis to the corresponding PUFA diols by soluble epoxide hydrolase. Inhibitors of soluble epoxide hydrolase stabilize PUFA epoxides and potentiate their functional effects. The epoxyeicosatrienoic acids (EETs) synthesized from arachidonic acid produce vasodilation, stimulate angiogenesis, have anti-inflammatory actions, and protect the heart against ischemia-reperfusion injury. EETs produce these functional effects by activating receptor-mediated signaling pathways and ion channels. The epoxyeicosatetraenoic acids synthesized from eicosapentaenoic acid and epoxydocosapentaenoic acids synthesized from docosahexaenoic acid are potent inhibitors of cardiac arrhythmias. Epoxydocosapentaenoic acids also inhibit angiogenesis, decrease inflammatory and neuropathic pain, and reduce tumor metastasis. These findings indicate that a number of the beneficial functions of PUFA may be due to their conversion to PUFA epoxides.

show abstract

“…2, the availability of EETs to these metabolic pathways increases when sEH is inhibited (16). The 22-carbon elongation product of 14,15-EET, which is an epoxide derivative of adrenic acid, relaxes bovine coronary artery preparations by hyperpolarizing smooth muscle in a manner similar to EETs (17).…”

Section: Eet Synthesis Metabolism and Functionmentioning

confidence: 99%

Arachidonic acid cytochrome P450 epoxygenase pathway

Spector

2009

Journal of Lipid Research

357

311

View full text Add to dashboard Cite

Cytochrome P450 (CYP) epoxygenases convert arachidonic acid to four epoxyeicosatrienoic acid (EET) regioisomers, 5,6-, 8,9-, 11,12-, and 14,15-EET, that function as autacrine and paracrine mediators. EETs produce vascular relaxation by activating smooth muscle large-conductance Ca 21 -activated K 1 channels (BK Ca ). In addition, they have anti-inflammatory effects on blood vessels and in the kidney, promote angiogenesis, and protect ischemic myocardium and brain. CYP epoxygenases also convert eicosapentaenoic acid to vasoactive epoxy-derivatives, and endocannabinoids containing 11,12-and 14,15-EET are formed. Many EET actions appear to be initiated by EET binding to a membrane receptor that activates ion channels and intracellular signal transduction pathways. However, EETs also are taken up by cells, are incorporated into phospholipids, and bind to cytosolic proteins and nuclear receptors, suggesting that some functions may occur through direct interaction of the EET with intracellular effector systems. Soluble epoxide hydrolase (sEH) converts EETs to dihydroxyeicosatrienoic acids (DHETs). Because this attenuates many of the functional effects of EETs, sEH inhibition is being evaluated as a mechanism for increasing and prolonging the beneficial actions of EETs. Epoxyeicosatrienoic acids (EET) are epoxide derivatives of arachidonic acid. They are formed by cytochrome P450 (CYP) epoxygenases and function as lipid mediators. Epoxidation can occur at any of the four double bonds of arachidonic acid, giving rise to four regioisomers, 5,6-, 8,9-, 11,12-, and 14,15-EET. EETs are synthesized in the endothelium and activate large-conductance Ca 21 -activated K 1 channels (BK Ca ), causing hyperpolarization of the vascular smooth muscle and vasorelaxation. Thus, EETs function as an endothelium-derived hyperpolarizing factor (EDHF) in a number of vascular beds, including the coronary and renal circulations, producing a decrease in blood pressure. Soluble epoxide hydrolase (sEH), which converts EETs to dihydroxyeicosatrienoic acids (DHETs), attenuates many of the functional effects of EETs. These seminal findings have been described in a number of detailed reviews (1-4). Recent results with cultured cells and animal models indicate that EETs have additional potentially beneficial effects on the vascular system, heart, kidneys, and nervous system, and many current studies are directed at these actions (5-9). The other current emphasis is on sEH inhibition as a therapeutic strategy for increasing the beneficial effects of EETs (10, 11). EET SYNTHESIS, METABOLISM, AND FUNCTIONEETs are synthesized by cells that express CYP epoxygenase activity. As illustrated in Fig. 1, these enzymes act on arachidonic acid released from phospholipids when cytosolic phospholipase A 2 (cPLA 2 ) is activated (12). The epoxygenase inserts an oxygen atom on a carbon attached to one of the double bonds of arachidonic acid, and the double bond is reduced as the epoxide forms. Each CYP epoxygenase produces several regioisomers, with one for...

show abstract

Metabolism of adrenic acid to vasodilatory 1α,1β-dihomo-epoxyeicosatrienoic acids by bovine coronary arteries

Cited by 30 publications

References 24 publications

Adrenic Acid Metabolites as Endogenous Endothelium-Derived and Zona Glomerulosa-Derived Hyperpolarizing Factors

Adrenic Acid Metabolites as Endogenous Endothelium-Derived and Zona Glomerulosa-Derived Hyperpolarizing Factors

Cytochrome P450 epoxygenase pathway of polyunsaturated fatty acid metabolism

Arachidonic acid cytochrome P450 epoxygenase pathway

Contact Info

Product

Resources

About