Platelet Aggregation Evoked In Vitro and In Vivo by Phosphatidic Acids and Lysoderivatives: Identity with Substances in Aged Serum (DAS)

K, Schumacher; Classen, H. G.; Späth, M.

doi:10.1055/s-0038-1666902

Cited by 125 publications

(77 citation statements)

References 4 publications

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“…2 Briefly, oleoyl chloride was acylated using 1-aminopropanol and pyridine followed by Dess-Martin oxidation. The resulting aldehyde was reacted with di-tbutylphosphonate in the presence of NaOH to generate the protected ␣-hydroxy derivative.…”

Section: Methodsmentioning

confidence: 99%

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Lysophosphatidic Acid-induced Mitogenesis Is Regulated by Lipid Phosphate Phosphatases and Is Edg-receptor Independent

Hooks¹,

Santos²,

Im³

et al. 2001

Journal of Biological Chemistry

126

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Lysophosphatidic acid (LPA) is an extracellular signaling mediator with a broad range of cellular responses. Three G-protein-coupled receptors (Edg-2, -4, and -7) have been identified as receptors for LPA. In this study, the ectophosphatase lipid phosphate phosphatase 1 (LPP1) has been shown to down-regulate LPAmediated mitogenesis. Furthermore, using degradationresistant phosphonate analogs of LPA and stereoselective agonists of the Edg receptors we have demonstrated that the mitogenic and platelet aggregation responses to LPA are independent of Edg-2, -4, and -7. Specifically, we found that LPA degradation is insufficient to account for the decrease in LPA potency in mitogenic assays, and the stereoselectivity observed at the Edg receptors is not reflected in mitogenesis. Additionally, RH7777 cells, which are devoid of Edg-2, -4, and -7 receptor mRNA, have a mitogenic response to LPA and LPA analogs. Finally, we have determined that the ligand selectivity of the platelet aggregation response is consistent with that of mitogenesis, but not with Edg-2, -4, and -7.The structurally simple phospholipid lysophosphatidic acid (LPA, 1 1-acyl, 2-hydroxy-sn-glycerol-3-phosphate) has been shown in the past decades to mediate an array of biological responses that is anything but simple. LPA has been shown to signal such vital cellular events as mitogenesis (1), platelet aggregation (2), tumor cell invasion (3), and escape from apoptosis (4). LPA is present in serum at low (1-20 M) micromolar concentrations (5) and is produced and released by stimulated platelets (6). The autocrine activation of platelet aggregation, coupled with LPA's mitogenic effects on smooth muscle cells (7) and fibroblasts (8), suggests a functional role for LPA as a wound-healing hormone (see review (9)). Furthermore, LPA accumulates to high concentrations in ovarian cancer ascitic fluid and is mitogenic to ovarian cancer cells, implicating LPA as a marker and mediator of ovarian cancer progression (10).In Recently, specific G-protein-coupled receptors for LPA have been identified within a cluster of eight related receptors termed the Edg (Endothelial differentiation gene) cluster. To date, eight members of the Edg cluster have been described. Edg-2 (15, 19), -4 (20), and -7 (21, 22) have been shown to be LPA receptors and Edg-1 (23, 24), -3, -5 (25), -6 (26, 27), and -8 (28) are receptors for the structurally related phospholipid sphingosine 1-phosphate. The LPA receptors differ with respect to distribution and G-protein coupling. Edg-2 is widely expressed, with highest mRNA levels appearing in brain (20), reflecting expression in Schwann cells and oligodendrocytes (29,30). Edg-4 is most highly expressed in testis and leukocytes (20), whereas Edg-7 is very highly expressed in kidney and prostate (21,22). When stably transfected into the LPA-unresponsive cell line RH7777 (Rat Hepatoma), Edg-2 mediates inhibition of cAMP accumulation, whereas Edg-4 and Edg-7 mediate calcium mobilization (22). Because only the inhibition of cAMP accumulation is pertus...

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Section: Methodsmentioning

confidence: 99%

“…LPA has been shown to signal such vital cellular events as mitogenesis (1), platelet aggregation (2), tumor cell invasion (3), and escape from apoptosis (4). LPA is present in serum at low (1-20 M) micromolar concentrations (5) and is produced and released by stimulated platelets (6).…”

mentioning

confidence: 99%

Lysophosphatidic Acid-induced Mitogenesis Is Regulated by Lipid Phosphate Phosphatases and Is Edg-receptor Independent

Hooks¹,

Santos²,

Im³

et al. 2001

Journal of Biological Chemistry

126

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“…[7][8][9] In contrast, high micromolar concentrations of LPA are required to induce aggregation of platelet-rich plasma. [10][11][12] In the present study we investigated whether and through which mechanism LPA could induce platelet shape change and aggregation in whole blood. We also studied the formation of platelet-monocyte aggregates, an early marker of acute myocardial infarction.…”

Section: Introductionmentioning

confidence: 99%

“…It induced thromboembolism. 10 Interestingly, only human and cat platelets are sensitive to LPA. Platelets from other species such as pig, dog, rabbit, rat, and, very importantly, the mouse cannot be activated by LPA in vitro (Schumacher et al 10 and Tokumura et al 11 ).…”

mentioning

confidence: 99%

The plaque lipid lysophosphatidic acid stimulates platelet activation and platelet-monocyte aggregate formation in whole blood: involvement of P2Y1 and P2Y12 receptors

Haserück

Erl

Pandey

et al. 2004

Blood

112

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Despite the fact that lysophosphatidic acid (LPA) has been identified as a main platelet-activating lipid of mildly oxidized low-density lipoprotein (LDL) and human atherosclerotic lesions, it remains unknown whether it is capable of activating platelets in blood. We found that LPA at concentrations slightly above plasma levels induces platelet shape change, aggregation, and platelet-monocyte aggregate formation in blood. 1-alkyl-LPA (16:0 fatty acid) was almost 20-fold more potent than 1-acyl-LPA (16:0). LPA directly induced platelet shape change in blood and platelet-rich plasma obtained from all blood donors. However, LPA-stimulated platelet aggregation in blood was donor dependent. It could be completely blocked by apyrase and antagonists of the platelet adenosine diphosphate (ADP) receptors P2Y 1 and P2Y 12 . These substances also inhibited LPA-induced aggregation of platelet-rich plasma and aggregation and serotonin secretion of washed platelets. These results indicate a central role for ADP-mediated P2Y 1 and P2Y 12 receptor activation in supporting LPA-induced platelet aggregation. Platelet aggregation and platelet-monocyte aggregate formation stimulated by LPA was insensitive to inhibition by aspirin. We conclude that LPA at concentrations approaching those found in vivo can induce platelet shape change, aggregation, and platelet-monocyte aggregate formation in whole blood and suggest that antagonists of platelet P2Y 1 and P2Y 12 receptors might be useful preventing LPA-elicited thrombus formation in patients with cardiovascular

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“…Plusieurs années après, en 1978, il fut montré que l'injection intraveineuse de LPA conduisait à des effets rapides sur la pression artérielle [2]. À la même période, le LPA, connu comme un puissant facteur pro-agrégant [3], était mis en évidence dans le sang lors de l'agrégation plaquettaire [4]. Les effets biologiques engendrés par le LPA bioactif ne résultaient pas d'une perturbation non spécifique de la structure de la membrane cellulaire due à une possible action détergente (propriété classique de certains lysophospholipides), mais de la mise en jeu probable d'un récepteur.…”

unclassified

L’acide lysophosphatidique : un phospholipide « bioactif »

Saulnier-Blache

2004

Med Sci (Paris)

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Platelet Aggregation Evoked In Vitro and In Vivo by Phosphatidic Acids and Lysoderivatives: Identity with Substances in Aged Serum (DAS)

Cited by 125 publications

References 4 publications

Lysophosphatidic Acid-induced Mitogenesis Is Regulated by Lipid Phosphate Phosphatases and Is Edg-receptor Independent

Lysophosphatidic Acid-induced Mitogenesis Is Regulated by Lipid Phosphate Phosphatases and Is Edg-receptor Independent

The plaque lipid lysophosphatidic acid stimulates platelet activation and platelet-monocyte aggregate formation in whole blood: involvement of P2Y1 and P2Y12 receptors

L’acide lysophosphatidique : un phospholipide « bioactif »

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