Regional biosynthesis of prostaglandins and hydroxyeicosatetraenoic acids from arachidonic acid in the rat stomach tissue

Purpose: Hyperhomocysteinemia (HHcy) has been considered a risk factor for different diseases including cardiovascular disease (CVD), inflammation, neurological diseases, cancer and many other pathological conditions. Likewise, arachidonic acid (AA) metabolism is implicated in both vascular homeostasis and inflammation as shown by the development of CVD following the imbalance of its metabolites. Aim of The Review: This review summarizes how homocysteine (Hcy) can influence the metabolism of AA. Methods: In silico literature searches were performed on PubMed and Scopus as main sources. Results: Several studies have shown that altered levels of Hcy, through AA release and metabolism, can influence the synthesis and the activity of prostaglandins (PGs), prostacyclin (PGI₂), thromboxane (TXA), epoxyeicosatrienoic acids (EETs) and hydroxyeicosatetraenoic acids (HETEs). Conclusions: We believe that by targeting Hcy in AA pathways, novel compounds with better pharmacological and pharmacodynamics benefits may be obtained and that this information is valuable for dietician to manipulate diets to improve health.

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Comparison of kinins derived from rat stomach tissue and produced by catheptic enzyme in rat stomach.

The Japanese Journal of Pharmacology ◽

10.1254/jjp.36.169 ◽

1984 ◽

Vol 36 (2) ◽

pp. 169-175 ◽

Cited By ~ 1

Author(s):

Motoki KOBAYASHI ◽

Katsuya OHATA

Keyword(s):

Rat Stomach ◽

Stomach Tissue

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Regulation of macrophage eicosanoid production by hydroperoxy-and hydroxy-eicosatetraenoic acids

Biochemical Journal ◽

10.1042/bj2330199 ◽

1986 ◽

Vol 233 (1) ◽

pp. 199-206 ◽

Cited By ~ 49

Author(s):

J L Humes ◽

E E Opas ◽

M Galavage ◽

D Soderman ◽

R J Bonney

Keyword(s):

Cell Culture ◽

Arachidonic Acid ◽

Peritoneal Macrophages ◽

Lipoxygenase Pathway ◽

Reversible Inhibitors ◽

Irreversible Inhibitors ◽

Intracellular Regulation ◽

Macrophage Populations ◽

Mouse Peritoneal Macrophages ◽

Hydroxyeicosatetraenoic Acids

Resident mouse peritoneal macrophages when exposed to zymosan during the first day of cell culture synthesize and secrete large amounts of prostaglandin E2 (PGE2) and leukotriene C4 (LTC4), the respective products of cyclo-oxygenase- and 5-lipoxygenase-catalysed oxygenations of arachidonic acid. Under these conditions of cell stimulation only small amounts of hydroxyeicosatetraenoic acids (HETEs) are concomitantly produced. However, exogenously added arachidonic acid is metabolized to large amounts of 12- and 15-HETE and only relatively small amounts of PGE2. No LTC4 is formed under these conditions. In contrast, resident mouse peritoneal macrophages in cell culture for 4 days synthesized less PGE2 and LTC4 when exposed to zymosan. However, these macrophage populations continue to synthesize 12-HETE from exogenously added arachidonic acid. Zymosan induced the secretion of a lysosomal enzyme, N-acetyl-beta-glucosaminidase, equally in both 1- and 4-day cultures. Both 12- and 15-hydroperoxyeicosatetraenoic acids (HPETEs), the precursors of 12- and 15-HETE, were found to be irreversible inhibitors of the cyclo-oxygenase pathway and reversible inhibitors of the 5-lipoxygenase pathway in macrophages. 15-HETE were found to be reversible inhibitors of both pathways. Thus the oxidation of arachidonic oxidation of arachidonic acid to both prostaglandins and leukotrienes may be under intracellular regulation by products of 12- and 15-lipoxygenases.

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Biochemistry of the lipoxygenase pathways in neutrophils

Canadian Journal of Physiology and Pharmacology ◽

10.1139/y89-147 ◽

1989 ◽

Vol 67 (8) ◽

pp. 936-942 ◽

Cited By ~ 26

Author(s):

Pierre Borgeat

Keyword(s):

Arachidonic Acid ◽

Ring Opening ◽

Arachidonic Acid Metabolism ◽

Biologically Active ◽

Eicosatetraenoic Acid ◽

Major Pathway ◽

Inflammatory Reactions ◽

Conjugated Triene ◽

Hydroxyeicosatetraenoic Acids ◽

Active Substances

Three mammalian lipoxygenases have been reported to date. They catalyze the insertion of oxygen at positions 5, 12, and 15 of various 20-carbon polyunsaturated fatty acids. In the case of arachidonic acid, the immediate products are hydroperoxyeicosatetraenoic acids (HPETEs). HPETEs can undergo different transformations. One reaction is a reduction of the hydroperoxy group yielding the corresponding hydroxyeicosatetraenoic acids (HETEs). In the neutrophils, the major pathway of arachidonic acid metabolism is the 5-lipoxygenase. In these cells the 5-HPETE undergoes a cyclization reaction leading to a 5(6)-epoxy(oxido)eicosatetraenoic acid or leukotriene A4. The 5(6)-epoxy fatty acid can undergo three additional transformations: (a) a nonenzymatic hydrolysis to epimeric dihydroxyeicosatetraenoic acids (diHETEs); (b) stereospecific enzymatic hydrolysis to a specific diHETE, leukotriene B4; or (c) ring opening by reduced glutathione (GSH) to yield a peptidolipid, named leukotriene C4, in which GSH is attached via a sulfoether linkage. The leukotrienes constitute a group of biologically active substances probably involved in allergic and inflammatory reactions. The 5(6)-epoxy-eicosatetraenoic acid and the products derived from it contain a conjugated triene unit; the term leukotriene also denotes the cells (leukocytes) recognized to form these products, mainly the neutrophils, eosinophils, basophils, monocytes, mast cells, and macrophages. In the present article various aspects of the biochemistry of the lipoxygenase pathways of neutrophils are reviewed.Key words: arachidonic acid, leukotrienes, leukocytes, lipoxygenase, inflammation.

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Metabolism of Arachidonic Acid to Epoxyeicosatrienoic Acids. Hydroxyeicosatetraenoic Acids, and Prostaglandins in Cultured Rat Hippocampal Astrocytes

Journal of Neurochemistry ◽

10.1111/j.1471-4159.1993.tb03550.x ◽

1993 ◽

Vol 61 (1) ◽

pp. 150-159 ◽

Cited By ~ 94

Author(s):

Shivachar C. Amruthesh ◽

Markus F. Boerschel ◽

Jerry S. McKinney ◽

Karen A. Willoughby ◽

Earl F. Ellis

Keyword(s):

Arachidonic Acid ◽

Epoxyeicosatrienoic Acids ◽

Hippocampal Astrocytes ◽

Hydroxyeicosatetraenoic Acids

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Preferential increase in prostaglandin endoperoxide H synthase compared with lipoxygenase activity in sheep placenta and amnion at term pregnancy and after intrafetal glucocorticoid administration

Journal of Endocrinology ◽

10.1677/joe.0.1390195 ◽

1993 ◽

Vol 139 (2) ◽

pp. 195-204 ◽

Cited By ~ 11

Author(s):

D. A. Langlois ◽

L. J. Fraher ◽

M. W. Khalil ◽

M. Fraser ◽

J. R. G. Challis

Keyword(s):

Arachidonic Acid ◽

Late Pregnancy ◽

Mean Value ◽

Arachidonic Acid Metabolism ◽

Arachidonic Acid Content ◽

Lipoxygenase Products ◽

Specific Increase ◽

Endoperoxide H Synthase ◽

Term Labour ◽

Hydroxyeicosatetraenoic Acids

ABSTRACT Prostaglandins (PGs) have been implicated as stimulants to myometrial contractility at parturition in many species. To determine whether the increased production of PGs at parturition reflects a general increase in the metabolism of arachidonic acid or a specific increase in PG endoperoxide H synthase (PGHS) compared with lipoxygenase activities, and to determine intrauterine sites of these activities, we examined the metabolism of [3H]arachidonic acid by homogenates of placenta, amnion and chorion from sheep at days 78–80, 100–105, 135–140 of pregnancy and at term (day 145). Tissues were also obtained from fetuses at day 125; four of these were infused for 84 h with cortisol and four were used as saline-treated controls. The endogenous arachidonic acid content at the start of incubation was measured by capillary gas chromatography. Radioactive metabolites were separated and quantified by reverse-phase high-pressure liquid chromatography. At each gestational age arachidonic acid was converted to PGs, leukotrienes (LTs) and hydroxyeicosatetraenoic acids (HETEs). Conversion to PGs was greater in amnion than in chorion or placenta between days 78 and 140. The formation of PGs rose in placenta at term to a mean value twice that of amnion and ten times that of chorion. In amnion, the ratio of PG: LT rose significantly at term relative to 100–140 days of gestation. In placenta, the ratio of PG: LT produced from arachidonic acid and the ratio of total PGHS: lipoxygenase products rose significantly at term. In the day-125 fetuses treated with cortisol there was a significant increase in PG production relative to that in control fetuses infused with saline in placenta, amnion and chorion; the placenta and amnion being the major sites of PG production. Production of LTs and HETEs also rose significantly in the chorion and the placenta relative to controls. In both the placenta and the amnion there was a significant increase in the ratio of total PGHS to lipoxygenase products formed. We conclude that at term labour and in labour induced by intrafetal cortisol infusion, the placenta is the major site of arachidonic acid metabolism, and that there is a preferential increase in the formation of PGs over lipoxygenase products. These results are consistent with the suggestion that there is an increase in the expression or activity of PGHS in the placenta of sheep in late pregnancy. Journal of Endocrinology (1993) 139, 195–204

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Angiotensin II-induced Akt activation is mediated by metabolites of arachidonic acid generated by CaMKII-stimulated Ca2+-dependent phospholipase A2

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.00571.2004 ◽

2005 ◽

Vol 288 (5) ◽

pp. H2306-H2316 ◽

Cited By ~ 26

Author(s):

Fang Li ◽

Kafait U. Malik

Keyword(s):

Arachidonic Acid ◽

Angiotensin Ii ◽

Ang Ii ◽

Akt Phosphorylation ◽

Akt Activation ◽

Interfering Rna ◽

Relationship Of ◽

The Relationship ◽

Cytochrome P 450 ◽

Hydroxyeicosatetraenoic Acids

Angiotensin II (ANG II) promotes vascular smooth muscle cell (VSMC) growth, stimulates Ca2+-calmodulin (CaM)-dependent kinase II (CaMKII), and activates cytosolic Ca2+-dependent phospholipase A2 (cPLA2), which releases arachidonic acid (AA). ANG II also generates H2O2 and activates Akt, which have been implicated in ANG II actions in VSMC. This study was conducted to investigate the relationship of these signaling molecules to Akt activation in rat aortic VSMC. ANG II increased Akt activity, as measured by its phosphorylation at serine-473. ANG II (200 nM)-induced Akt phosphorylation was decreased by extracellular Ca2+ depletion and calcium chelator EGTA and inhibitors of CaM [ N-(6-aminohexyl)-5-chloro-1-naphthalenesulfonamide] and CaMKII {(2-[ N-(2-hydroxyethyl)]- N-(4-me-thoxybenzenesulfonyl)]amino- N-(4-chlorocinnamyl)- N-methylbenzyl-amine)}. cPLA2 inhibitor pyrrolidine-1, antisense oligonucleotide, and retroviral small interfering RNA also attenuated ANG II-induced Akt phosphorylation. AA increased Akt phosphorylation, and AA metabolism inhibitor 5,8,11,14-eicosatetraynoic acid (ETYA) blocked ANG II- and AA-induced Akt phosphorylation (199.03 ± 27.91% with ANG II and 110.18 ± 22.40% with ETYA + ANG II; 405.00 ± 86.22% with AA and 153.97 ± 63.26% with ETYA + AA). Inhibitors of lipoxygenase (cinnamyl-3,4-dihydroxy-α-cyanocinnamate) and cytochrome P-450 (ketoconazole and 17-octadecynoic acid), but not cyclooxygenase (indomethacin), attenuated ANG II- and AA-induced Akt phosphorylation. Furthermore, 5( S)-, 12( S)-, 15( S)-, and 20-hydroxyeicosatetraenoic acids and 5,6-, 11,12-, and 14,15-epoxyeicosatrienoic acids increased Akt phosphorylation. Catalase inhibited ANG II-increased H2O2 production but not Akt phosphorylation. Oleic acid, which also increased H2O2 production, did not cause Akt phosphorylation. These data suggest that ANG II-induced Akt activation in VSMC is mediated by AA metabolites, most likely generated via lipoxygenase and cytochrome P-450 consequent to AA released by CaMKII-activated cPLA2 and independent of H2O2 production.

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