Manipulation of platelet aggregation by prostaglandins and their fatty acid precursors: Pharmacological basis for a therapeutic approach

Needleman, Philip; Whitaker, Mark; Wyche, Angela; Watters, K.; Sprecher, Howard; Raz, Amiram

doi:10.1016/0090-6980(80)90163-x

Cited by 118 publications

(29 citation statements)

References 24 publications

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“…PGE, and PGE, do have different biologic activities. For example, PGE, inhibits aggregation of human platelets in vitro whereas PGE, has no effect (26), and PGE, causes relaxation of uterine muscle arterioles whereas PGE, causes contraction of these arterioles. In addition, PGE, is far more effective than PGE, in increasing cyclic AMP in human synovial cells (25,27).…”

Section: Discussionmentioning

confidence: 99%

Alteration of the cellular fatty acid profile and the production of eicosanoids in human monocytes by gamma‐linolenic acid

Pullman-Mooar

Laposata

Lem

et al. 1990

Arthritis & Rheumatism

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We administered borage seed oil (9 capsules/day) for 12 weeks to 7 normal controls and to 7 patients with active rheumatoid arthritis. The therapy provided 1.1 gm/day of y-linolenic acid (GLA). GLA administration resulted in increased proportions of its first metabolite, dihomo-y-linolenic acid (DGLA), in circulating mononuclear cells. The ratios of DGLA to arachidonic acid and DGLA to stearic acid increased significantly in these cells. Significant reductions in prostaglandin E,, leukotriene B,, and leukotriene C, produced by stimulated monocytes were seen after 12 weeks of GLA supplementation. The antiintlammatory effects of GLA administration observed in animal models, and the apparent clinical improvement experienced by 6 of 7 rheumatoid arthritis patients given borage seed oil in this open,

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Section: Discussionmentioning

confidence: 99%

Alteration of the cellular fatty acid profile and the production of eicosanoids in human monocytes by gamma‐linolenic acid

Pullman-Mooar

Laposata

Lem

et al. 1990

Arthritis & Rheumatism

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“…In contrast, EPA, an n-3 essential fatty acid found in relative abundance in fish oil, appears to provide some protection from coronary thrombosis. EPA, like AA, is stored at the sn-2 position of phosphoglycerides and like AA can be released upon activation of phospholipases A 2 (1,17,38,45,47). For example, in circulating platelets EPA can be converted to the prostanoid PGH 3 , which, in turn, can be isomerized to thromboxane A 3 and PGD 3 (1,7,38).…”

Section: Prostaglandin Endoperoxide H Synthase (Pghs)mentioning

confidence: 99%

“…For example, in circulating platelets EPA can be converted to the prostanoid PGH 3 , which, in turn, can be isomerized to thromboxane A 3 and PGD 3 (1,7,38). However, EPA is both a poor substrate for platelet PGHS-1 and a potent competitive inhibitor of AA oxygenation by platelet PGHS-1 (1,17,38). Thus, the net effect of increased dietary intake of fish oil is to reduce the production of pro-thombogenic thromboxane from AA.…”

Section: Prostaglandin Endoperoxide H Synthase (Pghs)mentioning

confidence: 99%

“…EPA, like AA, is stored at the sn-2 position of phosphoglycerides and like AA can be released upon activation of phospholipases A 2 (1,17,38,45,47). For example, in circulating platelets EPA can be converted to the prostanoid PGH 3 , which, in turn, can be isomerized to thromboxane A 3 and PGD 3 (1,7,38). However, EPA is both a poor substrate for platelet PGHS-1 and a potent competitive inhibitor of AA oxygenation by platelet PGHS-1 (1,17,38).…”

Section: Prostaglandin Endoperoxide H Synthase (Pghs)mentioning

confidence: 99%

“…are derived from AA (37)(38)(39)(40). Linoleic acid (LA; 18 -2 n-6) and eicosapentaenoic acid (EPA; 20:5 n-3) are oxygenated via the cyclooxygenase activity of PGHSs by intact cells both in vitro and in vivo (41)(42)(43)(44)(45)(46)(47).…”

Section: Prostaglandin Endoperoxide H Synthase (Pghs)mentioning

confidence: 99%

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Structure of Eicosapentaenoic and Linoleic Acids in the Cyclooxygenase Site of Prostaglandin Endoperoxide H Synthase-1

Malkowski

Thuresson

Lakkides

et al. 2001

Journal of Biological Chemistry

116

101

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Prostaglandin endoperoxide H synthases-1 and -2 (PGHSs) can oxygenate 18 -22 carbon polyunsaturated fatty acids, albeit with varying efficiencies. Here we report the crystal structures of eicosapentaenoic acid (EPA, 20:5 n-3) and linoleic acid (LA, 18:2 n-6) bound in the cyclooxygenase active site of Co 3؉ protoporphyrin IX-reconstituted ovine PGHS-1 (Co 3؉ -oPGHS-1) and compare the effects of active site substitutions on the rates of oxygenation of EPA, LA, and arachidonic acid (AA). Both EPA and LA bind in the active site with orientations similar to those seen previously with AA and dihomo-␥-linolenic acid (DHLA). For EPA, the presence of an additional double bond (C-17/C-18) causes this substrate to bind in a "strained" conformation in which C-13 is misaligned with respect to Tyr-385, the residue that abstracts hydrogen from substrate fatty acids. Presumably, this misalignment is responsible for the low rate of EPA oxygenation. Prostaglandin endoperoxide H synthase (PGHS)1 converts arachidonic acid (AA) to prostaglandin H 2 in the committed step of prostaglandin and thromboxane biosynthesis (1, 2). Two isoforms of PGHS exist in mammalian tissues. PGHS-1 is constitutively expressed and generates prostaglandins in response to hormone stimulation, whereas PGHS-2 is an inducible enzyme that is expressed in response to growth factors, tumor promotors, or cytokines (1-11). Both isoforms are quite similar structurally (12-15) and mechanistically (1, 2, 16), with only subtle kinetic differences in substrate (17, 18) and inhibitor (19, 20) specificities, and hydroperoxide activator requirements (21-23).Both PGHS-1 and -2 catalyze two different reactions: a cyclooxygenase reaction and a peroxidase reaction. Structural studies indicate that the active sites are spatially distinct from each other and separated by a heme group (12-15). The cyclooxygenase reaction occurs within a hydrophobic channel that extends from the membrane binding domain of the enzyme into the core of the globular domain. The fatty acid substrate is positioned within this site in an extended L-shaped conformation (15,24). Cyclooxygenase catalysis begins with abstraction of the 13-pro-S hydrogen from AA by a tyrosyl radical centered on Tyr-385 in the rate-determining step to generate an arachidonyl radical (25-27). Two molecules of O 2 are then sequentially added to the arachidonyl radical to form the bicyclic hydroperoxide prostaglandin G 2 (PGG 2 ). This intermediate diffuses to the peroxidase active site where the 15-hydroperoxyl group undergoes a two-electron reduction to the alcohol prostaglandin H 2 . Although the peroxidase activity can function independently of the cyclooxygenase activity (28), activation of the cyclooxygenase requires a functional peroxidase (1,2,23).AA is the preferred substrate for PGHS-1 and PGHS-2 (17). Both isoforms will, however, oxygenate a variety of n-3 and n-6 18 -22 carbon fatty acids albeit with reduced catalytic efficiencies (17, 29 -36). Most of these alternative fatty acid substrates have somewhat higher K m...

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Suppression of human synovial cell proliferation by dihomo‐γ‐linolenic acid

Baker¹,

Krakauer²,

Tate³

et al. 1989

Arthritis & Rheumatism

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Prostaglandin E1 (PGE1) and oils enriched in its precursor fatty acids suppress inflammation and joint tissue injury in several animal models. Since synovial cell proliferation is a hallmark of rheumatoid arthritis, we studied the effect of dihomo‐γ‐linolenic acid (DGLA), an immediate precursor of PGE1, on the growth of human adherent synovial cells (ASC) in tissue culture. When stimulated by appropriate concentrations of recombinant interleukin‐1β (rIL‐1β), ASC proliferate and produce PGE. DGLA‐enriched medium suppressed both baseline and rIL‐1β–stimulated ASC growth fivefold, compared with medium supplemented with arachidonic acid. Indomethacin reduced the effect of the DGLA. Synovial cells incorporated the DGLA, and rIL‐1β–stimulated cells that were incubated with DGLA exhibited a 14‐fold increase in PGE1 (to 25.2 ± 6.0 ng/ml, mean ± SD) and a 70% decrease in PGE2 (to 25.2 ± 4.2 ng/ml) compared with cells in control medium. At equivalent concentrations (5 × 10−7M), PGE1 increased the level of cellular cAMP to a greater extent than did PGE2 (16.8 ± 2.0 pmoles versus 4.3 ± 1.9 pmoles, mean ± SEM). Exogenous PGE1 was also a more effective inhibitor of cell growth. Similarly, cAMP concentrations in cells exposed to DGLA for 6 hours were greater than concentrations in arachidonic acidenriched cultures (17.8 ± 3.3 pmoles versus 2.1 ± 2.0 pmoles). These observations suggest that DGLA can restrain ASC growth, an effect which may be due to its capacity to increase PGE1 production and subsequent cellular cAMP concentration.

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Manipulation of platelet aggregation by prostaglandins and their fatty acid precursors: Pharmacological basis for a therapeutic approach

Cited by 118 publications

References 24 publications

Alteration of the cellular fatty acid profile and the production of eicosanoids in human monocytes by gamma‐linolenic acid

Alteration of the cellular fatty acid profile and the production of eicosanoids in human monocytes by gamma‐linolenic acid

Structure of Eicosapentaenoic and Linoleic Acids in the Cyclooxygenase Site of Prostaglandin Endoperoxide H Synthase-1

Suppression of human synovial cell proliferation by dihomo‐γ‐linolenic acid

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