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Hammarström, Sven
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Publications (10 of 30) Show all publications
Ström, J., Strid, T. & Hammarström, S. (2012). Disruption of the alox5ap gene ameliorates focal ischemic stroke: possible consequence of impaired leukotriene biosynthesis. BMC neuroscience (Online), 13, 146
Open this publication in new window or tab >>Disruption of the alox5ap gene ameliorates focal ischemic stroke: possible consequence of impaired leukotriene biosynthesis
2012 (English)In: BMC neuroscience (Online), ISSN 1471-2202, E-ISSN 1471-2202, Vol. 13, p. 146-Article in journal (Refereed) Published
Abstract [en]

Background

Leukotrienes are potent inflammatory mediators, which in a number of studies have been found to be associated with ischemic stroke pathology: gene variants affecting leukotriene synthesis, including the FLAP (ALOX5AP) gene, have in human studies shown correlation to stroke incidence, and animal studies have demonstrated protective properties of various leukotriene-disrupting drugs. However, no study has hitherto described a significant effect of a genetic manipulation of the leukotriene system on ischemic stroke. Therefore, we decided to compare the damage from focal cerebral ischemia between wild type and FLAP knockout mice. Damage was evaluated by infarct staining and a functional test after middle cerebral artery occlusion in 20 wild type and 20 knockout male mice.

Results

Mortality-adjusted median infarct size was 18.4 (3.2-76.7) mm3 in the knockout group, compared to 72.0 (16.7-174.0) mm3 in the wild type group (p < 0.0005). There was also a tendency of improved functional score in the knockout group (p = 0.068). Analysis of bone marrow cells confirmed that knockout animals had lost their ability to form leukotrienes.

Conclusions

Since the local inflammatory reaction after ischemic stroke is known to contribute to the brain tissue damage, the group difference seen in the current study could be a consequence of a milder inflammatory reaction in the knockout group. Our results add evidence to the notion that leukotrienes are important in ischemic stroke, and that blocked leukotriene production ameliorates cerebral damage.

Place, publisher, year, edition, pages
BioMed Central, 2012
Keywords
Brain infarction, Leukotrienes, Alox5ap protein, FLAP, Mice, Middle cerebral artery occlusion
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-89759 (URN)10.1186/1471-2202-13-146 (DOI)000314271500001 ()23194405 (PubMedID)
Note

Funding Agencies|Elvar and Annette Theodorsson||Marta Lundqvists stiftelse||County Council of Ostergotland||

Available from: 2013-03-05 Created: 2013-03-05 Last updated: 2017-12-06Bibliographically approved
Börjesson, S., Parkkari, T., Hammarström, S. & Elinder, F. (2010). Electrostatic Tuning of Cellular Excitability. Biophysical Journal, 98(3), 396-403
Open this publication in new window or tab >>Electrostatic Tuning of Cellular Excitability
2010 (English)In: Biophysical Journal, ISSN 0006-3495, E-ISSN 1542-0086, Vol. 98, no 3, p. 396-403Article in journal (Refereed) Published
Abstract [en]

Voltage-gated ion channels regulate the electric activity of excitable tissues, such as the heart and brain. Therefore, treatment for conditions of disturbed excitability is often based on drugs that target ion channels. In this study of a voltage-gated K channel, we propose what we believe to be a novel pharmacological mechanism for how to regulate channel activity. Charged lipophilic substances can tune channel opening, and consequently excitability, by an electrostatic interaction with the channels voltage sensors. The direction of the effect depends on the charge of the substance. This was shown by three compounds sharing an arachiclonyl backbone but bearing different charge: arachidonic acid, methyl arachidonate, and arachidonyl amine. Computer simulations of membrane excitability showed that small changes in the voltage dependence of Na and K channels have prominent impact on excitability and the tendency for repetitive firing. For instance, a shift in the voltage dependence of a K channel with -5 or +5 mV corresponds to a threefold increase or decrease in K channel density, respectively. We suggest that electrostatic tuning of ion channel activity constitutes a novel and powerful pharmacological approach with which to affect cellular excitability.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-54082 (URN)10.1016/j.bpj.2009.10.026 (DOI)000274313200006 ()
Note

Original Publication: Sara Börjesson, Teija Parkkari, Sven Hammarström and Fredrik Elinder, Electrostatic Tuning of Cellular Excitability, 2010, BIOPHYSICAL JOURNAL, (98), 3, 396-403. http://dx.doi.org/10.1016/j.bpj.2009.10.026 Copyright: Elsevier Science B.V., Amsterdam http://www.elsevier.com/

Available from: 2010-02-22 Created: 2010-02-22 Last updated: 2018-01-25Bibliographically approved
Strid, T., Svartz, J., Franck, N., Hallin, E., Ingelsson, B., Söderström, M. & Hammarström, S. (2009). Distinct parts of leukotriene C-4 synthase interact with 5-lipoxygenase and 5-lipoxygenase activating protein. Biochemical and Biophysical Research Communications - BBRC, 381(4), 518-522
Open this publication in new window or tab >>Distinct parts of leukotriene C-4 synthase interact with 5-lipoxygenase and 5-lipoxygenase activating protein
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2009 (English)In: Biochemical and Biophysical Research Communications - BBRC, ISSN 0006-291X, E-ISSN 1090-2104, Vol. 381, no 4, p. 518-522Article in journal (Refereed) Published
Abstract [en]

Leukotriene C-4 is a potent inflammatory mediator formed from arachidonic acid and glutathione. 5-Lipoxygenase (5-LO), 5-lipoxygenase activating protein (FLAP) and leukotriene C-4 synthase (LTC4S) participate in its biosynthesis. We report evidence that LTC4S interacts in vitro with both FLAP and 5-LO and that these interactions involve distinct parts of LTC4S. FLAP bound to the N-terminal part/first hydrophobic region of LTC4S. This part did not bind 5-LO which bound to the second hydrophilic loop of LTC4S. Fluorescent FLAP- and LTC4S-fusion proteins co-localized at the nuclear envelope. Furthermore, GFP-FLAP and GFP-LTC4S co-localized with a fluorescent ER marker. In testing HEK293/T or COS-7 cells GFP-5-LO was found mainly in the nuclear matrix. Upon stimulation with calcium ionophore, GFP-5-LO translocated to the nuclear envelope allowing it to interact with FLAP and LTC4S. Direct interaction of 5-LO and LTC4S in ionophore-stimulated (but not un-stimulated) cells was demonstrated by BRET using GFP-5-LO and Rluc-LTC4S.

Keywords
BRET, Confocal fluorescence microscopy, Eicosanoids, Fusion proteins, GFP, GST pull-down assay, Nuclear envelope
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-17904 (URN)10.1016/j.bbrc.2009.02.074 (DOI)000264929400013 ()
Note

Original Publication: Tobias Strid, Jesper Svartz, Niclas Franck, Elisabeth Hallin, Björn Ingelsson, Mats Söderström and Sven Hammarström, Distinct parts of leukotriene C-4 synthase interact with 5-lipoxygenase and 5-lipoxygenase activating protein, 2009, BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS, (381), 4, 518-522. http://dx.doi.org/10.1016/j.bbrc.2009.02.074 Copyright: Elsevier Science B.V., Amsterdam http://www.elsevier.com/

Available from: 2009-04-30 Created: 2009-04-24 Last updated: 2017-12-13Bibliographically approved
Strid, T., Karlsson, C., Söderström, M., Zhang, J., Qian, H., Sigvardsson, M. & Hammarström, S. (2009). Fetal hepatic expression of 5-lipoxygenase activating protein is confined to colonizing hematopoietic cells. Biochemical and Biophysical Research Communications - BBRC, 383(3), 336-339
Open this publication in new window or tab >>Fetal hepatic expression of 5-lipoxygenase activating protein is confined to colonizing hematopoietic cells
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2009 (English)In: Biochemical and Biophysical Research Communications - BBRC, ISSN 0006-291X, E-ISSN 1090-2104, Vol. 383, no 3, p. 336-339Article in journal (Refereed) Published
Abstract [en]

Leukotriene C-4 is a potent inflammatory mediator formed from arachidonic acid and glutathione. 5-Lipoxygenase (540), 5-lipoxygenase activating protein (FLAP) and leukotriene C-4 synthase (LTC4S) participate in its biosynthesis. We report evidence from in situ hybridization experiments that FLAP mRNA is abundantly expressed in fetal mouse liver from e11.5 until delivery. In contrast very little or no FLAP mRNA was detected in adult liver. The fetal expression in liver was not uniform but occurred in patches. Cells from e15.5 livers were fractionated by fluorescence activated cell sorting into hepatocytes and other CD45(-) cells and CD45(+) hematopoietic cells. The latter were further separated into immature (Lin(-)) and mature (Lin(+)) cells and analyzed for FLAP mRNA content by quantitative RT-PCR. FLAP mRNA expression was confined to CD45(+) cells and the mature cells had approximately 4-fold higher FLAP mRNA levels compared to the immature cells.

Keywords
Embryonic development, Fluorescence-activated cell sorting, In situ hybridization, Leukotrienes, 5-Lipoxygenase activating protein, Liver, Hematopoietic cells
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-18568 (URN)10.1016/j.bbrc.2009.04.007 (DOI)000265966800012 ()
Available from: 2009-06-01 Created: 2009-06-01 Last updated: 2017-12-13Bibliographically approved
Strid, T., Söderström, M. & Hammarström, S. (2008). Leukotriene C4 synthase promoter driven expression of GFP reveals cell specificity. Biochemical and Biophysical Research Communications - BBRC, 366(1), 80-85
Open this publication in new window or tab >>Leukotriene C4 synthase promoter driven expression of GFP reveals cell specificity
2008 (English)In: Biochemical and Biophysical Research Communications - BBRC, ISSN 0006-291X, E-ISSN 1090-2104, Vol. 366, no 1, p. 80-85Article in journal (Refereed) Published
Abstract [en]

Leukotriene C4 synthase is a key enzyme in leukotriene biosynthesis. Its gene has been cloned and mapped to mouse chromosome 11. Expression occurs in cells of myeloid origin and also in the choroid plexus, the hypothalamus and the medial eminence of mouse brain. In this study a vector that expresses enhanced green fluorescent protein (eGFP) under the control of the mouse leukotriene C4 synthase promoter was constructed and used to study promoter activity in different cell lines. Specific eGFP expression was observed in human monocytic leukemia (THP-1) and rat basophilic leukemia (RBL-1) myeloid cells which both express leukotriene C4 synthase, but not in human embryonic kidney (HEK293/T) epithelial cells which do not express this enzyme. In the myeloid cells, but not in the epithelial cells, we observed that the leukotriene C4 synthase promoter activity was stimulated by 12-O-tetradecanoylphorbol-13-acetate and all-trans-retinoic acid. In contrast dimethyl sulfoxide did not affect promoter activity. © 2007 Elsevier Inc. All rights reserved.

Keywords
Leukotriene; Leukotriene C4 synthase; Expression; GFP; TPA; Promoter; Retinoic acid; DMSO
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-42196 (URN)10.1016/j.bbrc.2007.11.097 (DOI)000252392400013 ()61334 (Local ID)61334 (Archive number)61334 (OAI)
Available from: 2009-10-10 Created: 2009-10-10 Last updated: 2017-12-13Bibliographically approved
Börjesson, S., Hammarström, S. & Elinder, F. (2008). Lipoelectric modification of ion channel voltage gating by polyunsaturated fatty acids. Biophysical Journal, 95(5), 2242-2253
Open this publication in new window or tab >>Lipoelectric modification of ion channel voltage gating by polyunsaturated fatty acids
2008 (English)In: Biophysical Journal, ISSN 0006-3495, E-ISSN 1542-0086, Vol. 95, no 5, p. 2242-2253Article in journal (Refereed) Published
Abstract [en]

Polyunsaturated fatty acids (PUFAs) have beneficial effects on epileptic seizures and cardiac arrhythmia. We report that ω-3 and ω-6 all-cis-PUFAs affected the voltage dependence of the Shaker K channel by shifting the conductance versus voltage and the gating charge versus voltage curves in negative direction along the voltage axis. Uncharged methyl esters of the PUFAs did not affect the voltage dependence, whereas changes of pH and charge mutations on the channel surface affected the size of the shifts. This suggests an electrostatic effect on the channel's voltage sensors. Monounsaturated and saturated fatty acids, as well as trans-PUFAs did not affect the voltage dependence. This suggests that fatty acid tails with two or more cis double bonds are required to place the negative carboxylate charge of the PUFA in a position to affect the channel's voltage dependence. We propose that charged lipophilic compounds could play a role in regulating neuronal excitability by electrostatically affecting the channel's voltage sensor. We believe this provides a new approach for pharmacological treatment that is voltage sensor pharmacology. © 2008 by the Biophysical Society.

Keywords
Animals Docosahexaenoic Acids/metabolism Electrophysiology Fatty Acids, Unsaturated/analysis/*physiology Hydrogen-Ion Concentration Ion Channel Gating/*physiology Magnesium/physiology Membrane Potentials Oocytes/*physiology Patch-Clamp Techniques Shaker S
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-43208 (URN)10.1529/biophysj.108.130757 (DOI)72950 (Local ID)72950 (Archive number)72950 (OAI)
Available from: 2009-10-10 Created: 2009-10-10 Last updated: 2018-01-25Bibliographically approved
Svensson Holm, A.-C., Berg, C., Herbertsson, H., Söderström, M., Hammarström, S., Lindström, E. & Bengtsson, T. (2006). 5-Lipoxygenase activity is involved in platelet-induced fibroblast proliferation. Paper presented at Kardiovaskulära vårmötet, Linköping.
Open this publication in new window or tab >>5-Lipoxygenase activity is involved in platelet-induced fibroblast proliferation
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2006 (English)Conference paper, Published paper (Refereed)
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-69447 (URN)
Conference
Kardiovaskulära vårmötet, Linköping
Available from: 2011-06-28 Created: 2011-06-28 Last updated: 2013-10-23
Svensson Holm, A.-C., Berg, C., Herbertsson, H., Söderström, M., Hammarström, S., Lindström, E. & Bengtsson, T. (2006). 5-Lipoxygenase activity is involved in platelet-induced fibroblast proliferation. Paper presented at XIV International Symposium on Atherosclerosis, Rom.
Open this publication in new window or tab >>5-Lipoxygenase activity is involved in platelet-induced fibroblast proliferation
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2006 (English)Conference paper, Published paper (Refereed)
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-69442 (URN)
Conference
XIV International Symposium on Atherosclerosis, Rom
Available from: 2011-06-28 Created: 2011-06-28 Last updated: 2013-10-23
Svartz, J., Hallin, E., Shi, Y., Söderström, M. & Hammarström, S. (2006). Identification of regions of leukotriene C4 synthase which direct the enzyme to its nuclear envelope localization. Journal of Cellular Biochemistry, 98(6), 1517-1527
Open this publication in new window or tab >>Identification of regions of leukotriene C4 synthase which direct the enzyme to its nuclear envelope localization
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2006 (English)In: Journal of Cellular Biochemistry, ISSN 0730-2312, E-ISSN 1097-4644, Vol. 98, no 6, p. 1517-1527Article in journal (Refereed) Published
Abstract [en]

Leukotrienes (LTs) are fatty acid derivatives formed by oxygenation of arachidonic acid via the 5-lipoxygenase (5-LO) pathway. Upon activation of inflammatory cells 5-LO is translocated to the nuclear envelope (NE) where it converts arachidonic acid to the unstable epoxide LTA4. LTA4 is further converted to LTC4 by conjugation with glutathione, a reaction catalyzed by the integral membrane protein LTC4 synthase (LTC4S), which is localized on the NE and endoplasmic reticulum (ER). We now report the mapping of regions of LTC4S that are important for its subcellular localization. Multiple constructs encoding fusion proteins of green fluorescent protein (GFP) as the N-terminal part and various truncated variants of human LTC4S as C-terminal part were prepared and transfected into HEK 293/T or COS-7 cells. Constructs encoding hydrophobic region 1 of LTC4S (amino acids 6–27) did not give distinct membrane localized fluorescence. In contrast hydrophobic region 2 (amino acids 60–89) gave a localization pattern similar to that of full length LTC4S. Hydrophobic region 3 (amino acids 114–135) directed GFP to a localization indistinguishable from that of full length LTC4S. A minimal directing sequence, amino acids 117–132, was identified by further truncation. The involvement of the hydrophobic regions in the homo-oligomerization of LTC4S was investigated using bioluminescence resonance energy transfer (BRET) analysis in living cells. BRET data showed that hydrophobic regions 1 and 3 each allowed oligomerization to occur. These regions most likely form transmembrane helices, suggesting that homo-oligomerization of LTC4S is due to helix–helix interactions in the membrane.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-36053 (URN)10.1002/jcb.20880 (DOI)000239469800013 ()29608 (Local ID)29608 (Archive number)29608 (OAI)
Available from: 2009-10-10 Created: 2009-10-10 Last updated: 2018-03-19Bibliographically approved
Berg, C., Hammarström, S., Herbertsson, H., Lindström, E., Svensson, A.-C., Söderström, M., . . . Bengtsson, T. (2006). Platelet-induced growth of human fibroblasts is associated with an increased expression of 5-lipoxygenase. Thrombosis and Haemostasis, 96(5), 652-659
Open this publication in new window or tab >>Platelet-induced growth of human fibroblasts is associated with an increased expression of 5-lipoxygenase
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2006 (English)In: Thrombosis and Haemostasis, ISSN 0340-6245, Vol. 96, no 5, p. 652-659Article in journal (Refereed) Published
Abstract [en]

Proliferation of fibroblasts is vital for adequate wound healing but is probably also involved in different hyperproliferative disorders such as atherosclerosis and cancer. The regeneration of tissue usually starts with coagulation, involving release of mitogenic and inflammatory factors from activated platelets. This study focuses on the role of eicosanoids in the proliferative effects of platelets on human fibroblasts. We show that the phospholipase A2 inhibitor 7,7-dimethyl-5,8-eicosadienoic acid (DMDA), the combined cyclooxygenase (COX) and lipoxygenase (LOX) inhibitor 5,8,11,14-eicosatetraynoic acid (ETYA) and the LOX inhibitor 5,8,11-eicosatriynoic acid (ETI) block the platelet-induced proliferation of serum starved subconfluent human fibroblasts. Anti-proliferative effects were also obtained by specific inhibition of 5-LOX with 5,6-dehydro arachidonic acid (5,6-dAA), whereas the 12-LOX inhibitor cinnamyl-3,4-dihydroxy-α-cyanocinnamate (CDC) did not affect the platelet-stimulated growth of fibroblasts. The expression of 5-LOX was analyzed by reverse-transcriptase-mediated PCR (RT-PCR), Western blotting and HPLC. 5-LOX message and protein was detected in fibroblasts but not in platelets. Incubation with platelets markedly increased, already after one hour, the expression of 5-LOX in the fibroblast culture. The increased 5-LOX activity was associated with an elevated level of the 5-LOX metabolite 5-hydroxyeicosatetraenoic acid (5-HETE) reaching its maximum after 1-2 hours of co-incubation of fibroblasts and platelets. The 5-HETE production was reduced by the inhibitors DMDA, ETYA and ETI. In conclusion, this study suggests that platelet-stimulated proliferation of fibroblasts is mediated by an increased 5-LOX activity, which supports recent findings indicating a crucial role for this enzyme in proliferative disorders such as atherosclerosis. © 2006 Schattauer GmbH, Stuttgart.

National Category
Natural Sciences
Identifiers
urn:nbn:se:liu:diva-36111 (URN)10.1160/TH06-02-0069 (DOI)000242168400016 ()29986 (Local ID)29986 (Archive number)29986 (OAI)
Available from: 2009-10-10 Created: 2009-10-10 Last updated: 2017-12-13
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