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Inhibition of Ca2 +/calmodulin-dependent protein kinase or epidermal growth factor receptor tyrosine kinase abolishes lysophosphatidic acid-mediated DNA-synthesis in human myometrial smooth muscle cells
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.
2003 (English)In: Cell Biology International, ISSN 1065-6995, Vol. 27, no 4, 341-347 p.Article in journal (Refereed) Published
Abstract [en]

Human myometrial smooth muscle cells (SMCs) were used to evaluate the proliferative activity of lysophosphatidic acid (LPA). This study specifically focuses on the role of Ca2+/calmodulin-dependent protein (CaM) kinase and epidermal growth factor (EGF) receptor tyrosine kinase. Myometrial SMCs were cultured from biopsies taken at Cesarean sections. The expression of LPA receptors was determined by reverse transcriptase polymerase chain reaction (RT-PCR), and DNA-synthesis was measured by [3H]thymidine incorporation. LPA1, LPA2, and LPA3receptor subtypes were detected in the SMCs using RT-PCR. KN-62, an inhibitor of CaM kinase, and Tyrphostin AG 1478, an inhibitor of EGF receptor tyrosine kinase, dose-dependently decreased LPA-stimulated [3H]thymidine incorporation. Furthermore, BB-3103, an inhibitor of matrix metalloproteinases (MMPs), also reduced DNA-synthesis induced by LPA in these cells. The results show, for the first time, that human myometrial SMCs express all three known LPA receptor subtypes. Growth stimulatory effects of LPA on myometrial SMCs seems to be mediated by several pathways, where transactivation of EGF receptors through MMPs appears to be of importance. Furthermore, CaM kinase activity may be critical for LPA signaling since inhibition of CaM kinase totally abolish the proliferative effect of LPA.

Place, publisher, year, edition, pages
2003. Vol. 27, no 4, 341-347 p.
Keyword [en]
Calcium, Calmodulin, DNA-synthesis, Epidermal growth factor, Lysophosphatidic acid, Smooth muscle cells
National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:liu:diva-13737DOI: 10.1016/S1065-6995(02)00352-9OAI: oai:DiVA.org:liu-13737DiVA: diva2:21227
Available from: 2006-01-17 Created: 2006-01-17
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.Svensson, Samuel P.S.

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