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Synergistic activation of human platelets by adrenaline and lysophosphatidic acid
Linköping University, Department of Medicine and Health Sciences, Pharmacology . Linköping University, Faculty of Health Sciences.
Linköping University, Department of Medicine and Health Sciences, Pharmacology . Linköping University, Faculty of Health Sciences.
Linköping University, Department of Medicine and Health Sciences, Pharmacology . Linköping University, Faculty of Health Sciences.
2002 (English)In: Haematologica, ISSN 0390-6078, Vol. 87, no 7, 730-739 p.Article in journal (Refereed) Published
Abstract [en]

BACKGROUND AND OBJECTIVES: Platelet reactivity is regulated by various important bioactive and physiologic substances. The objective of this study was to characterize lysophosphatidic acid (LPA)-triggered responses in human platelets. In addition, the effect of LPA was compared with that of other activators and possible synergistic interactions were evaluated.

DESIGN AND METHODS: LPA-triggered cytosolic Ca(2+) responses were measured using fura-2-loaded platelets in a spectrofluorometer. Furthermore, platelet aggregation and secretion were analyzed in a lumi-aggregometer and protein tyrosine phosphorylation was detected with the Western blot technique.

RESULTS: LPA dose-dependently increased cytosolic Ca(2+) concentration ([Ca(2+)](i)) in platelets. This response involved both influx of extracellular Ca(2+) and release of Ca(2+) from intracellular stores. However, in comparison with other platelet agonists, i.e. thrombin and adenosine 5'-diphosphate (ADP), LPA was a very weak Ca(2+)-elevating agent. Furthermore, we observed that the LPA-induced rise in [Ca(2+)](i) was markedly suppressed by cyclic nucleotide-elevating agents. In functional studies, LPA failed to stimulate platelet aggregation and secretion. However, in combination with adrenaline, another weak platelet agonist, LPA could induce an irreversible and complete aggregatory response. There was an individual variation in aggregatory response and tyrosine phosphorylation when LPA and adrenaline were combined. These agents induced a powerful response on platelets from some individuals, but had a weak or no effect on others.

INTERPRETATION AND CONCLUSIONS: The present study shows, for the first time, that isolated platelets from some healthy blood donors respond synergistically to a combination of LPA and adrenaline. Platelet activation is a key step in distinguishing normal hemostasis from pathologic hemostasis. Increased knowledge about this mechanism might help to predict individual responses and provide new insights into molecular mechanisms responsible for pathologic thrombosis.

Place, publisher, year, edition, pages
2002. Vol. 87, no 7, 730-739 p.
National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:liu:diva-13738OAI: oai:DiVA.org:liu-13738DiVA: diva2:21228
Available from: 2006-01-17 Created: 2006-01-17 Last updated: 2009-05-28
In thesis
1. Lysophosphatidic acid: Physiological effects and structure-activity relationships
Open this publication in new window or tab >>Lysophosphatidic acid: Physiological effects and structure-activity relationships
2002 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Lipids havepreviously been considered primarily as building blocks of the cell membrane, but are now also recognized as important cell signaling molecules. Lysophosphatidic acid (LPA) is a glycerophospholipid consisting of a phosphate head group, a linker region, and a lipophilic tail. LPA has earlier been shown to exert a diversity of cellular effects such as aggregation, apoptosis, contraction, migration, and proliferation. The effects of LPA are elicited by activation of its cognate G protein-coupled receptors LPA1, LPA2, and LPA3. In the present study we have used cultures of human smooth muscle cells (SMCs) and erythroleukemia cells (HEL), and isolated human platelets to characterize physiological effects of LPA compared with adrenaline and noradrenaline as well as structure-activity relationships of LPA. SMCs were isolated from biopsies of human myometrium obtained at cesarean sections. We show that cultured myometrial SMCs express multiple LPA and α2-adrenergic receptor subtypes. Treatment of SMCs with LPA and noradrenaline resulted in increases in proliferation. However, LPA elicits a much more pronounced stimulatory effect than noradrenaline. The ability to increase calcium might be one explanation why LPA is more effective. Further studies indicated that several pathways mediate the growth stimulatory effect of LPA where transactivation of epidermal growth factor receptors through matrix metalloproteinases as well as calcium/calmodulin-dependent protein kinases appears to be important. LPA enantiomers and LPA analogues were synthesized and characterized due to their capacity to increase calcium in HEL cells. Our study is the first to show that both natural (R) and unnatural (S) LPA enantiomers are capable of stimulating cells, suggesting LPA receptors are not stereoselective. Moreover, we have synthesized a LPA analogue with higher maximal effect than LPA by reducing the hydrocarbon chain length. In platelets we demonstrated that LPA is a weak calciumelevating compound which failed to stimulate aggregation. However, in combination with adrenaline, another weak platelet agonist, a complete aggregatory response was obtained in blood from some healthy individuals. These results are important since platelet activation is a key step in distinguishing normal from pathological hemostasis. Since LPA is present at high concentrations in atherosclerotic lesions, the synergistic effect of LPA and adrenaline might be a new risk factor for arterial thrombosis.

Place, publisher, year, edition, pages
Linköping: Linköping University Electronic Press, 2002. 100 p.
Series
Linköping University Medical Dissertations, ISSN 0345-0082 ; 751
Keyword
Lysophospholipids pharmacology, physiology, structure-activity relationship, muscle, smooth, drug effects, myometrium, norepinephrine, epinephrine, signal transduction
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-5237 (URN)91-7373-192-7 (ISBN)
Public defence
2002-11-08, Berzeliussalen, Campus US, Linköpings universitet, Linköping, 13:00 (English)
Opponent
Supervisors
Note
On the day of the public defence the status of the article IV was: Submitted for publication.Available from: 2006-01-17 Created: 2006-01-17 Last updated: 2012-01-25Bibliographically approved

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Nilsson, Ulrika K.Grenegård, MagnusSvensson, Samuel P.S.

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