Biosynthesis, catabolism, and biological properties of HPETEs, hydroperoxide derivatives of arachidonic acid

Pace-Asciak, Cecil R.; Asotra, Satish

doi:10.1016/0891-5849(89)90125-1

Cited by 77 publications

(19 citation statements)

References 161 publications

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“…Two lipoxygenase isoforms have been described in endothelial cells: 12-and 15-lipoxygenase, corresponding to the carbon where the oxygenation reaction occurs (13,28). These lipoxygenases convert AA to hydroperoxyeicosatetraenoic acids (HPETEs), which are unstable and rapidly reduced by cellular peroxidases to HETEs or by a heme-containing hydroperoxide isomerase to HEETAs (25). Hydrolysis of the epoxy group of the HEETA by an epoxide hydrolase results in the formation of THETAs (28).…”

Section: Discussionmentioning

confidence: 99%

Cyclooxygenase- and lipoxygenase-dependent relaxation to arachidonic acid in rabbit small mesenteric arteries

Zhang¹,

Gauthier²,

Chawengsub³

et al. 2005

American Journal of Physiology-Heart and Circulatory Physiology

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. Cyclooxygenase-and lipoxygenase-dependent relaxation to arachidonic acid in rabbit small mesenteric arteries. Am J Physiol Heart Circ Physiol 288: H302-H309, 2005. First published September 23, 2004; doi:10.1152/ ajpheart.00661.2004We recently reported that the lipoxygenase product 11,12,15-trihydroxyeicosatrienoic acid (THETA) mediates arachidonic acid (AA)-induced relaxation in the rabbit aorta. This study was designed to determine whether this lipoxygenase metabolite is involved in relaxation responses to AA in rabbit small mesenteric arteries. AA (10 Ϫ9 -10 Ϫ4 M) produced potent relaxations in isolated phenylephrine-preconstricted arteries, with a maximal relaxation of 99 Ϯ 0.5% and EC50 of 50 nM. The cyclooxygenase (COX) inhibitors indomethacin (10 M), NS-398 (10 M, selective for COX-2), and SC-560 (100 nM, selective for COX-1) caused a marked rightward shift of concentration responses to AA. With the use of immunohistochemical analysis, both COX-1 and COX-2 were detected in endothelium and smooth muscle of small mesenteric arteries. Indomethacin-resistant relaxations were further reduced by the lipoxygenase inhibitors cinnamyl-3,4-dihydroxy-cyanocinnamate (CDC; 1 M), nordihydroguaiaretic acid (NDGA; 1 M), and ebselen (1 M). HPLC analysis showed that [ 14 C]AA was metabolized by mesenteric arteries to PGI2, PGE2, THETAs, hydroxyepoxyeicosatrienoic acids (HEETAs), and 15-hydroxyeicosatetraenoic acid (15-HETE). The production of PGI2 and PGE2 was blocked by indomethacin, and the production of THETAs, HEETAs, and 15-HETE was inhibited by CDC and NDGA. Column fractions corresponding to THETAs were further purified, analyzed by gas chromatography/mass spectrometry, and identified as 11,12,15-and 11,14,15-THETA. PGI2, PGE2, and purified THETA fractions relaxed mesenteric arteries precontracted with phenylephrine. The AA-and THETA-induced relaxations were blocked by high K ϩ (60 mM). These findings provide functional and biochemical evidence that AA-induced relaxation in rabbit small mesenteric arteries is mediated through both COX and lipoxygenase pathways.endothelium-derived factors; trihydroxyeicosatrienoic acid; prostaglandin E2; prostaglandin I2; endothelium-derived hyperpolarizing factor ACETYLCHOLINE, BRADYKININ, AND OTHER VASODILATORS elicit endothelium-dependent relaxation by release of a number of soluble factors from the vascular endothelium (8,17,22,23). These relaxing factors include nitric oxide (NO), prostacyclin, and a group of compounds termed EDHFs. Although the chemical identity of EDHF remains controversial, its action has been demonstrated in a number of vascular beds, where a significant portion of endothelium-dependent relaxation persists in the presence of NO synthase (NOS) and cyclooxygenase (COX) inhibitors such as N-nitro-L-arginine (L-NNA) and indomethacin. This endothelium-dependent, non-NO, and nonprostacyclin relaxation is associated with smooth muscle hyperpolarization and is sensitive to K ϩ channel blockers such as apamin and charybdotoxin (7,9,14,16,24). The mediators of EDHF ...

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Section: Discussionmentioning

confidence: 99%

Cyclooxygenase- and lipoxygenase-dependent relaxation to arachidonic acid in rabbit small mesenteric arteries

Zhang¹,

Gauthier²,

Chawengsub³

et al. 2005

American Journal of Physiology-Heart and Circulatory Physiology

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“…Once available, these PUFAs can be oxygenated by two main routes: the cyclooxygenase pathway, which leads to the biologically active prostaglandins, and the lipoxygenase pathway, which is a complex of pathways leading to hydroperoxyeicosatetraenoic acids, hydroxyeicosatetraenoic acids, leukotrienes, lipoxins, and hepoxilins (13,14). Products of both pathways are important in various aspects of mammalian host defense.…”

Section: Discussionmentioning

confidence: 99%

Insect immune response to bacterial infection is mediated by eicosanoids.

Stanley-Samuelson

Jensen

Nickerson

et al. 1991

Proc. Natl. Acad. Sci. U.S.A.

156

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Inhibition of eicosanoid formation in larvae of the tobacco hornworm Manduca sexta, using specific inhibitors of phospholipase A2, cyclooxygenase, and lipoxygenase, severely weakened the ability of larvae to clear the bacterium Serratia marcescens from their hemolymph. The reduced capability to remove bacteria is associated with increased mortality due to these bacteria. There is a dose-dependent relationship between the phospholipase A2 inhibitor dexamethasone and both the reduced bacterial clearance and increased larval mortality. The dexamethasone effects on larval survival were reversed by treatment with arachidonic acid. Maleic acid, a nonspecific antioxidant, did not interfere with the insects' ability to remove bacterial cells from hemolymph. The larvae were shown to contain all of the C20 polyunsaturated fatty acids necessary for eicosanoid biosynthesis and to be capable of converting radioactive arachidonic acid into several primary prostaglandins. These results strongly suggest that eicosanoids mediate transduction of bacterial infection signals into the complex of cellular and humoral responses that comprise invertebrate immunity.Invertebrate immunity is an amalgam of several distinct systems, both cellular and humoral, that operate in a more or less coordinated way to provide protection from invading pathogens (1). Cellular responses include phagocytosis, encapsulation, and various cytotoxic reactions such as release of lysozyme (1, 2) and the prophenoloxidase activating system (3). These hemocyte-mediated responses are complemented by antibacterial activity, such as lectins, which occur constitutively in invertebrate hemolymph (4). In addition to normally occurring factors, several antibacterial peptides are induced by bacterial infections [namely, the cecropins (4 kDa), attacins (21 to 23 kDa), diptericins (8 kDa), and insect defensins (4 kDa)] (3,5).An important area of invertebrate immunity that has not been critically addressed concerns how the early responses to infection are mediated-that is, what is the sequence of biochemical events operative between microbial invasion and the appearance of defense mechanisms? To date, only two early steps in the immune response have been investigated. In one, immune-specific RNA was shown to be synthesized 2-4 hr after bacterial infection of the moths Hyalophora cecropia and Galleria mellonella (3). In the other, inducible lectins were synthesized in the flesh fly Sarcophaga peregrina almost immediately after their immune system was challenged (6). However, these genespecific events follow from earlier steps in transduction of bacterial invasion signals into physiological defense responses.Since many aspects of immunological defense in mammals are mediated by eicosanoid metabolites of arachidonic acid (7), we hypothesized that biosynthesis of eicosanoids is also an essential early step in mediation of the immune response in invertebrates. We tested this hypothesis by using an insect, the tobacco hornworm Manduca sexta. We report here that selective ...

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“…These may be metabolized further to various bioactive lipid mediators including leukotrienes, lipoxins, hydroxyeicosatetraenoic acids (HETEs), and hepoxilins (2). Although LOX enzymes are catalytically active with free fatty acid substrates, some will also oxygenate esterified substrates such as the phospholipid or cholesterol esters.…”

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confidence: 99%

The lipoxygenase gene ALOXE3 implicated in skin differentiation encodes a hydroperoxide isomerase

Schneider

Boeglin

et al. 2003

Proc. Natl. Acad. Sci. U.S.A.

138

152

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Herein we identify a logical link of the biochemistry to the genetics. eLOX3 functions as a hydroperoxide isomerase (epoxyalcohol synthase) by using the product of 12R-LOX as the preferred substrate. 12R-Hydroperoxyeicosatetraenoic acid (12R-HPETE) is converted to 8R-hydroxy-11R,12R-epoxyeicosa-5Z,9E,14Z-trienoic acid, one of the isomers of hepoxilin A 3, and to 12-ketoeicosatetraenoic acid in a 2:1 ratio. Other hydroperoxides, including 8R-HPETE, 12S-HPETE, and 15S-HPETE, as well as the 13S-and 13R-hydroperoxides of linoleic acid are converted less efficiently. Mass spectrometric analysis of the epoxyalcohol formed from [ 18 O]15S-HPETE showed that both hydroperoxy oxygens are retained in the product. We propose that the ferrous form of eLOX3 initiates a redox cycle, unprecedented among LOX in being autocatalytic, in which the hydroperoxy substrate is isomerized to the epoxyalcohol or keto product. Our results provide strong biochemical evidence for a functional linkage of 12R-LOX and eLOX3 and clues into skin biochemistry and the etiology of ichthyosiform diseases in humans. L ipoxygenases (LOXs) are a family of nonheme ironcontaining enzymes that oxygenate unsaturated fatty acids such as arachidonic acid to specific hydroperoxide products (1). These may be metabolized further to various bioactive lipid mediators including leukotrienes, lipoxins, hydroxyeicosatetraenoic acids (HETEs), and hepoxilins (2). Although LOX enzymes are catalytically active with free fatty acid substrates, some will also oxygenate esterified substrates such as the phospholipid or cholesterol esters. LOX metabolites play important roles in cell signaling or modification of membrane structures (1, 3).There are five active LOXs found in human beings: 5-LOX, 12S-LOX, 12R-LOX, 15-LOX-1, and 15-LOX-2. A sixth gene family member, epidermal LOX type 3 (eLOX3, gene symbol ALOXE3) was described first in the mouse (4), and in humans in 2001 (5). The amino acid sequence of human eLOX3 shows the closest similarity to 12R-LOX (54% identity) and 15-LOX-2 (51%). It contains the characteristic well conserved amino acid residues found in all LOXs including the putative iron-binding ligands and additional structure-determining residues. These features clearly indicate that eLOX3 belongs to the LOX gene family. The question of the catalytic activity of eLOX3, nonetheless, has remained elusive. No enzymatic activity has been detected by using linoleic or arachidonic acids, the prototypical C18 and C20 LOX substrates, nor with methyl arachidonate or cholesteryl arachidonate (4). In the first section of Results we confirm and extend these findings.Studies in humans and the mouse indicate that eLOX3 has a limited scope of tissue expression, being mainly confined to keratinized epithelia such as skin. From PCR evidence it seems to be coexpressed in tissues that express the 12R-LOX (5). A functional relationship to skin pathophysiology is strongly suggested by a recent genetic study reporting that eLOX3 or 12R-LOX are mutated in six families affected by nonbul...

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Biosynthesis, catabolism, and biological properties of HPETEs, hydroperoxide derivatives of arachidonic acid

Cited by 77 publications

References 161 publications

Cyclooxygenase- and lipoxygenase-dependent relaxation to arachidonic acid in rabbit small mesenteric arteries

Cyclooxygenase- and lipoxygenase-dependent relaxation to arachidonic acid in rabbit small mesenteric arteries

Insect immune response to bacterial infection is mediated by eicosanoids.

The lipoxygenase gene ALOXE3 implicated in skin differentiation encodes a hydroperoxide isomerase

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