Platelet aggregating activity of lysophosphatidic acids is not related to their calcium ionophore properties

Simon, Marie‐Pierre; Chap, Hugues; Douste‐Blazy, Louis

doi:10.1016/0014-5793(84)80055-1

Cited by 23 publications

(8 citation statements)

References 41 publications

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“…The contrasting effects of Oco2Gro and PMA on thrombin versus collagen-induced arachidonate release, with pre-incubation times of up to 5 min, may be related to the significant inhibition of thrombin-induced elevation in [Ca2+Ii levels by Oco2Gro and PMA, and the different [Ca2+Ii requirements for thrombin and collagen in the induction of arachidonate release [20,351. Thus, previous studies [20] as well as the results of the present study, have demonstrated the ability of collagen to induce arachidonate release without a rise in [Ca2+Ii levels, while this is not the case with thrombin [35]. On the other hand, potentiation of Ca2 +-ionophoreinduced arachidonate release by PMA [21] and Oco2Gro suggests that the effect of C kinase activators on agonistinduced arachidonate release may depend on two factors : firstly, on whether arachidonate release is dependent on [Ca2 ' Ii mobilisation, and secondly, whether [Ca2 +Ii mobilisation is inhibited by them.…”

Section: Discussionsupporting

confidence: 67%

1,2‐Dioctanoylglycerol but not 1‐oleoyl‐2‐acetylglycerol inhibits agonist‐induced platelet responses

Krishnamurthi

Joseph

Kakkar

1987

European Journal of Biochemistry

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1. The effect of the membrane-permeable diacylglycerol analogues, 1,2-dioctanoylglycero1 (OcozGro) and 1 -oleoyl-2-acetyl-glycerol (OleAcGro) on agonist-induced platelet activation processes were compared with those of the phorbol ester, phorbol12-myristate 13-acetate (PMA), using appropriately labelled washed human platelets.2. Pre-treatment (10 -300 s) with OcozGro (1 5 -60 pM) or PMA (16 nM) before addition of thrombin (0.2 U/ ml) or, addition of these agents 10-20 s after thrombin, resulted in a significant reduction (20-80%) in the extent of thrombin-induced intracellular CaZ ' ([Ca2'Ii) mobilisation and arachidonate/thromboxane B2 release.OleAcGro (62-125 pM) had no effect on thrombin-induced [Ca2+Ii elevations but had a slight (15%) inhibitory effect on thrombin-induced arachidonate release with a 5-min pre-incubation. Addition of OcozGro, PMA orOleAcGro on their own caused no rise in [Ca2 'Ii levels or arachidonate release.3. Collagen (20 pg/ml) induced substantial arachidonate release without a detectable rise in [Ca2+Ii. Pretreatment (10-300 s) with OcozGro (15-60 pM), PMA (16 nM) or OleAcGro (62 pM) before collagen addition or addition of these agents 30 -60 s after collagen addition resulted in a significant potentiation of arachidonate release (1.2 -2-fold over control), even though thromboxane B2 formation in response to collagen was inhibited in the presence of OcozGro or PMA.4. Both Oco2Gro and PMA had dual effects on 5-hydroxytryptamine secretion induced by thrombin or collagen. Short pre-incubations ( < 2 min) with these agents caused a potentiation of sub-maximal agonist-induced secretion, while not affecting secretion induced by maximal agonist concentrations. With longer pre-incubation times (5 -15 min) however, a significant reduction in the level of agonist-induced secretion in the presence of Oco2Gro or PMA was observed. Inhibition of secretion was also observed in platelets treated with indomethacin (10 pM), suggesting that inhibition of thromboxane B2 formation alone does not account for inhibition of 5-hydroxytryptamine secretion. OleAcGro had no inhibitory effects on agonist-induced secretion even though it potentiated it (with < 2-min incubations) at sub-maximal agonist concentrations.5. Time courses of phosphorylation of a 45-kDa protein, a marker of protein kinase C activation, in 32P-labelled platelets showed that while OcozGro (60 pM) and PMA (16 nM) caused a 4-5-fold increase in 32P-labelling of this protein over a 5-min incubation period, OleAcGro (62-125 pM) caused a 1.5-fold increase in labelling which was only maintained for a 10-30-s period. The inability of OleAcGro to exert any significant inhibitory effects on agonist-induced platelet responses may therefore be due to insufficient activation of protein kinase C and/or phosphorylation of the 45-kDa protein. Hence, OcozGro may be a better tool as a diacylglycerol analogue. However, the potentiatory effects of OleAcGro with short pre-incubations (agonist-induced 5-hydroxytryptamine secretion and collagen-induced arachidonat...

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Section: Discussionsupporting

confidence: 67%

1,2‐Dioctanoylglycerol but not 1‐oleoyl‐2‐acetylglycerol inhibits agonist‐induced platelet responses

Krishnamurthi

Joseph

Kakkar

1987

European Journal of Biochemistry

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“…So our present study confirms and extends these data by showing that PLC activation occurs in vivo at basal [Ca2+]i, which appears to be sufficient for the enzyme to operate. In addition to our recent work on the properties of lysophosphatidic acids [37], this would give further support to the hypothesis that PLC together with protein kinase C are involved in cell activation through a Ca2+-independent pathway [l l-131. It also fits with the proposed role of inositol-tri-phosphate, the liberation of which by PLC would trigger Ca*+ mobilization from an intracellular store [9].…”

Section: Discussionsupporting

confidence: 57%

Activation of phospholipase C in thrombin‐stimulated platelets does not depend on cytoplasmic free calcium concentration

1984

Self Cite

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Human platelets loaded with the fluorescent Ca2+ indicator quin2 and with different radioactive compounds including [3H]serotonin, [14C]arachidonic acid (AA) and [32P]orthophosphate were stimulated by thrombin under conditions producing secretion. In the absence of external Ca2' (Gag'), cytoplasmic free [Ca2'], [Ca2+]i, increased to 340 nM, against 1685 nM at 1 mM [CaL+le. In both cases, diglyceride and phosphatidic acid production proceeded at the same rate, whereas AA release was inhibited at low [Ca'+]i. It is concluded that, at variance with phospholipase AZ, phospholipase C activation does not depend on [Ca2+]r. These results give further support to the hypothesis of a Ca2+-independent pathway of cell activation involving phospholipase C and protein kinase C.

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“…These authors identified LPA as being one of the active factors and noted that it caused desensitization of the platelet response, a hallmark of GPCR action. Simon et al discovered that the alkyl-ether analogue of LPA is a potent activator of human platelets at concentrations as low as 10 -10 M, making this analogue nearly as potent as platelet-activating factor (Simon et al, 1982;1984). The barrier function of vascular endothelial cells is altered by LPA (Schulze et al, 1997;Alexander et al, 1998;English et al, 1999), and LPA induces the expression of VCAM-1 and E-selectin on the surface of cultured human endothelial cells (Rizza et al, 1999).…”

Section: Lpa In Reproductive Disordersmentioning

confidence: 99%

Aiming drug discovery at lysophosphatidic acid targets

Tigyi

2010

British J Pharmacology

164

151

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Lysophosphatidic acid (LPA, 1-radyl-2-hydroxy-sn-glycero-3-phosphate) is the prototype member of a family of lipid mediators and second messengers. LPA and its naturally occurring analogues interact with G protein-coupled receptors on the cell surface and a nuclear hormone receptor within the cell. In addition, there are several enzymes that utilize LPA as a substrate or generate it as a product and are under its regulatory control. LPA is present in biological fluids, and attempts have been made to link changes in its concentration and molecular composition to specific disease conditions. Through their many targets, members of the LPA family regulate cell survival, apoptosis, motility, shape, differentiation, gene transcription, malignant transformation and more. The present review depicts arbitrary aspects of the physiological and pathophysiological actions of LPA and attempts to link them with select targets. Many of us are now convinced that therapies targeting LPA biosynthesis and signalling are feasible for the treatment of devastating human diseases such as cancer, fibrosis and degenerative conditions. However, successful targeting of the pathways associated with this pleiotropic lipid will depend on the future development of as yet undeveloped pharmacons.

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Platelet aggregating activity of lysophosphatidic acids is not related to their calcium ionophore properties

Cited by 23 publications

References 41 publications

1,2‐Dioctanoylglycerol but not 1‐oleoyl‐2‐acetylglycerol inhibits agonist‐induced platelet responses

1,2‐Dioctanoylglycerol but not 1‐oleoyl‐2‐acetylglycerol inhibits agonist‐induced platelet responses

Activation of phospholipase C in thrombin‐stimulated platelets does not depend on cytoplasmic free calcium concentration

Aiming drug discovery at lysophosphatidic acid targets

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