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Svensson Holm, Ann-Charlotte B.
Alternative names
Publications (10 of 16) Show all publications
Södergren, A., Svensson Holm, A.-C., Ramström, S., Lindström, E., Grenegård, M. & Öllinger, K. (2016). Thrombin-induced lysosomal exocytosis in human platelets is dependent on secondary activation by ADP and regulated by endothelial-derived substances. Platelets, 27(1), 86-92
Open this publication in new window or tab >>Thrombin-induced lysosomal exocytosis in human platelets is dependent on secondary activation by ADP and regulated by endothelial-derived substances
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2016 (English)In: Platelets, ISSN 0953-7104, E-ISSN 1369-1635, Vol. 27, no 1, p. 86-92Article in journal (Refereed) Published
Abstract [en]

Exocytosis of lysosomal contents from platelets has been speculated to participate in clearance of thrombi and vessel wall remodelling. The mechanisms that regulate lysosomal exocytosis in platelets are, however, still unclear. The aim of this study was to identify the pathways underlying platelet lysosomal secretion and elucidate how this process is controlled by platelet inhibitors. We found that high concentrations of thrombin induced partial lysosomal exocytosis as assessed by analysis of the activity of released N-acetyl--glucosaminidase (NAG) and by identifying the fraction of platelets exposing the lysosomal-associated membrane protein (LAMP)-1 on the cell surface by flow cytometry. Stimulation of thrombin receptors PAR1 or PAR4 with specific peptides was equally effective in inducing LAMP-1 surface expression. Notably, lysosomal exocytosis in response to thrombin was significantly reduced if the secondary activation by ADP was inhibited by the P2Y(12) antagonist cangrelor, while inhibition of thromboxane A(2) formation by treatment with acetylsalicylic acid was of minor importance in this regard. Moreover, the NO-releasing drug S-nitroso-N-acetyl penicillamine (SNAP) or the cyclic AMP-elevating eicosanoid prostaglandin I-2 (PGI(2)) significantly suppressed lysosomal exocytosis. We conclude that platelet inhibitors that mimic functional endothelium such as PGI(2) or NO efficiently counteract lysosomal exocytosis. Furthermore, we suggest that secondary release of ADP and concomitant signaling via PAR1/4- and P2Y(12) receptors is important for efficient platelet lysosomal exocytosis by thrombin.

Place, publisher, year, edition, pages
TAYLOR & FRANCIS INC, 2016
Keywords
ADP receptors; endothelium; exocytosis; lysosome; platelet physiology; protease activated receptors (PAR); thrombin
National Category
Clinical Medicine Biological Sciences
Identifiers
urn:nbn:se:liu:diva-125318 (URN)10.3109/09537104.2015.1042446 (DOI)000368717700011 ()25970449 (PubMedID)
Note

Funding Agencies|County Council of Ostergotland; Swedish Research Council

Available from: 2016-02-24 Created: 2016-02-19 Last updated: 2018-10-25
Svensson Holm, A.-C., Grenegård, M., Ollinger, K. & Lindström, E. (2014). Inhibition of 12-lipoxygenase reduces platelet activation and prevents their mitogenic function. Platelets, 25(2), 111-117
Open this publication in new window or tab >>Inhibition of 12-lipoxygenase reduces platelet activation and prevents their mitogenic function
2014 (English)In: Platelets, ISSN 0953-7104, E-ISSN 1369-1635, Vol. 25, no 2, p. 111-117Article in journal (Refereed) Published
Abstract [en]

The aim of the present study was to investigate the role of 12-lipoxygenase (12-LOX) on platelet-induced airway smooth muscle cell (ASMC) proliferation. Co-incubation of platelets and ASMC caused platelet activation as determined by morphological changes. Simultaneously, reactive oxygen species (ROS)-generation was detected and ASMC proliferation (measured by using the MTS assay) increased significantly. Furthermore, we found that the 12-LOX inhibitors cinnamyl-3,4-dihydroxy-α-cyanocinnamate (CDC) and Baicalein prevented platelet activation in a co-cultures of platelets and ASMC. The inhibitory effect of CDC and Baicalein on platelets was also registered in a pure platelet preparation. Specifically, the 12-LOX inhibitors reduced collagen-induced platelet aggregation both in the presence and absence of external added fibrinogen. Importantly, platelet-induced ASMC proliferation and ROS production generated during the platelet/ASMC interaction was significantly inhibited in the presence of 12-LOX inhibitors. In conclusion, our findings reveal that 12-LOX is crucial for the observed enhancement of ASMC proliferation in co-cultures of platelets and ASMC. The present result suggests that 12-LOX activity is important in the initial step of platelet/ASMC interaction and platelet activation. Such action of 12-LOX represents a potential important mechanism that may contribute to platelet-induced airway remodelling.

Place, publisher, year, edition, pages
Informa Healthcare, 2014
Keywords
12-lipoxygenase, airway remodelling, airway smooth muscle, platelet-induced proliferation
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-99371 (URN)10.3109/09537104.2013.783688 (DOI)000331905100006 ()23534390 (PubMedID)
Available from: 2013-10-16 Created: 2013-10-16 Last updated: 2017-12-06Bibliographically approved
Svensson Holm, A.-C. B., Lindgren, I., Österman, H. & Altimiras, J. (2014). Thyroid hormone does not induce maturation of embryonicchicken cardiomyocytes in vitro. Physiological Reports, 2(12), e12182
Open this publication in new window or tab >>Thyroid hormone does not induce maturation of embryonicchicken cardiomyocytes in vitro
2014 (English)In: Physiological Reports, E-ISSN 2051-817X, Vol. 2, no 12, p. e12182-Article in journal (Refereed) Published
Abstract [sv]

Fetal cardiac growth in mammalian models occurs primarily by cell proliferation(hyperplasia). However, most cardiomyocytes lose the ability to proliferateclose to term and heart growth continues by increasing cell size(hypertrophy). In mammals, the thyroid hormone triiodothyronine (T3) is animportant driver of this process. Chicken cardiomyocytes, however, keep theirproliferating ability long after hatching but little information is available onthe mechanisms controlling cell growth and myocyte maturation in thechicken heart. Our aim was to study the role of T3 on proliferation and differentiationof embryonic chicken cardiomyocytes (ECCM), enzymaticallyisolated from 19-day-old embryos and to compare the effects to those of insulin-like growth factor-1 (IGF-1) and phenylephrine (PE). Hyperplasia wasmeasured using a proliferation assay (MTS) and hypertrophy/multinucleationwas analyzed morphologically by phalloidin staining of F-actin and nuclearstaining with DAPI. We show that IGF-1 induces a significant increase inECCM proliferation (30%) which is absent with T3 and PE. PE induced bothhypertrophy (61%) and multinucleation (41%) but IGF-1 or T3 did not. Inconclusion, we show that T3 does not induce maturation or proliferation ofcardiomyocytes, while IGF-1 induces cardiomyocyte proliferation and PEinduces maturation of cardiomyocytes.

Place, publisher, year, edition, pages
Wiley Periodicals, Inc., 2014
Keywords
Heart growth, hyperplasia, hypertrophy, insulin-like growth factor-1, thyroid hormone
National Category
Biological Sciences
Identifiers
urn:nbn:se:liu:diva-113604 (URN)10.14814/phy2.12182 (DOI)25501434 (PubMedID)
Available from: 2015-01-26 Created: 2015-01-26 Last updated: 2017-12-05Bibliographically approved
Svensson Holm, A.-C., Bengtsson, T., Grenegård, M. & Lindström, E. G. (2012). Hyaluronic acid influence on platelet-induced airway smooth muscle cell proliferation. Experimental Cell Research, 318(5), 632-640
Open this publication in new window or tab >>Hyaluronic acid influence on platelet-induced airway smooth muscle cell proliferation
2012 (English)In: Experimental Cell Research, ISSN 0014-4827, E-ISSN 1090-2422, Vol. 318, no 5, p. 632-640Article in journal (Refereed) Published
Abstract [en]

Hyaluronic acid (HA) is one of the main components of the extracellular matrix (ECM) and is expressed throughout the body including the lung and mostly in areas surrounding proliferating and migrating cells. Furthermore, platelets have been implicated as important players in the airway remodelling process, e.g. due to their ability to induce airway smooth muscle cell (ASMC) proliferation. The aim of the present study was to investigate the role of HA, the HA-binding surface receptor CD44 and focal adhesion kinase (FAK) in platelet-induced ASMC proliferation. Proliferation of ASMC was measured using the MTS-assay, and we found that the CD44 blocking antibody and the HA synthase inhibitor 4-Methylumbelliferone (4-MU) significantly inhibited platelet-induced ASMC proliferation. The interaction between ASMC and platelets was studied by fluorescent staining of F-actin. In addition, the ability of ASMC to synthesise HA was investigated by fluorescent staining using biotinylated HA-binding protein and a streptavidin conjugate. We observed that ASMC produced HA and that a CD44 blocking antibody and 4-MU significantly inhibited platelet binding to the area surrounding the ASMC. Furthermore, the FAK-inhibitor PF 573228 inhibited platelet-induced ASMC proliferation. Co-culture of ASMC and platelets also resulted in increased phosphorylation of FAK as detected by Western blot analysis. In addition, 4-MU significantly inhibited the increased FAK-phosphorylation. In conclusion, our findings demonstrate that ECM has the ability to influence platelet-induced ASMC proliferation. Specifically, we propose that HA produced by ASMC is recognised by platelet CD44. The platelet/HA interaction is followed by FAK activation and increased proliferation of co-cultured ASMC. We also suggest that the mitogenic effect of platelets represents a potential important and novel mechanism that may contribute to airway remodelling.

Place, publisher, year, edition, pages
Elsevier, 2012
Keywords
Airway smooth muscle; Airway remodelling; Extracellular matrix; Hyaluronic acid; CD44; Focal adhesion kinase; Platelets
National Category
Basic Medicine
Identifiers
urn:nbn:se:liu:diva-75382 (URN)10.1016/j.yexcr.2011.12.011 (DOI)000300966300021 ()22227408 (PubMedID)
Note
funding agencies|strategic areas Cardiovascular Inflammation Research Centre (CIRC)||Material in Medicine, the Heart- and Lung foundation||County of Ostergotlands Lan||STIFUD||Olle E||Swedish Research Council||Available from: 2012-02-28 Created: 2012-02-28 Last updated: 2018-01-12
Svensson Holm, A.-C. B., Bengtsson, T., Grenegård, M. & Lindström, E. G. (2011). Platelet membranes induce airway smooth muscle cellproliferation. Platelets, 22(1), 45-55
Open this publication in new window or tab >>Platelet membranes induce airway smooth muscle cellproliferation
2011 (English)In: Platelets, ISSN 0953-7104, E-ISSN 1369-1635, Vol. 22, no 1, p. 45-55Article in journal (Refereed) Published
Abstract [en]

The role of platelets in airway disease is poorly understood although they have been suggested to influence on proliferation of airway smooth muscle cells (ASMC). Platelets have been found localised in the airways in autopsy material from asthmatic patients and have been implicated in airway remodeling. The aim of the present study was to investigate the effects of various platelet fractions on proliferation of ASMC obtained from guinea pigs (GP-ASMC) and humans (H-ASMC). Proliferation of ASMC was measured by the MTS-assay and the results were confirmed by measurements of the DNA content. A key observation was that the platelet membrane preparations induced a significant increase in the proliferation of both GPASMC (129.9 ± 3.0 %) and H-ASMC (144.8 ± 12.2). However, neither supernatants obtained from lysed nor filtrate from thrombin stimulated platelets did induce ASMC proliferation to the same extent as the membrane preparation. We have previously shown the platelet-induced proliferation is dependent on the 5-lipoxygenase (5-LOX) and reactive oxygen species (ROS) pathways. In the present work we established that platelet membrane-induced ASMC proliferation was reduced in the presence of the NADPH oxidase inhibitor DPI and the 5-LOX inhibitor AA-861. In conclusion, our results showed that platelet  membranes significantly induced ASMC proliferation, demonstrating that the mitogenic effect of platelets and platelet membranes on ASMC is mainly due to membrane-associated factors. The effects of platelet membranes were evident on both GP-ASMC and H-ASMC and involved 5-LOX and ROS. These new findings are of importance in understanding the mechanisms contributing to airway remodeling and may contribute to the development of new pharmacological tools in the treatment of inflammatory airway diseases.

Place, publisher, year, edition, pages
Informa, 2011
Keywords
platelets; platelet membranes; airway smooth muscle cell; 5-lipoxygenase; reactive oxygen species; airway remodeling
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-61615 (URN)10.3109/09537104.2010.515696 (DOI)000286937800006 ()
Note
Original Publication: Ann-Charlotte B. Svensson Holm, Torbjörn Bengtsson, Magnus Grenegård and Eva G. Lindström, Platelet membranes induce airway smooth muscle cellproliferation, 2011, Platelets, (22), 1, 45-55. http://dx.doi.org/10.3109/09537104.2010.515696 Copyright: Informa Healthcare http://informahealthcare.com/ Available from: 2010-11-17 Created: 2010-11-17 Last updated: 2017-12-12
Svensson Holm, A.-C. B. (2010). Platelets and airway remodeling: Mechanisms involved in platelet-induced fibroblast and airway smooth muscle cell proliferation in vitro. (Doctoral dissertation). Linköping: Linköping University Electronic Press
Open this publication in new window or tab >>Platelets and airway remodeling: Mechanisms involved in platelet-induced fibroblast and airway smooth muscle cell proliferation in vitro
2010 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Airway remodeling is a contributing cause to the pathological structural changes, such as increased cell proliferation, observed in asthma. Platelets have been found in autopsy lungmaterial obtained from asthmatic patients and are well known to induce proliferation in vitro of a variety of cells. However, the role of platelets in airway remodeling is far from understood. This thesis aims to clarify the involvement of platelets in fibroblast and airway smooth muscle cell (ASMC) proliferation in vitro and to elucidate the importance of HA, FAK, eicosanoid and ROS dependent signaling. The results demonstrate that platelets induce ASMC proliferation through NADPH-oxidase and 5-LOX dependent mechanisms. In addition, platelets also induce a 5-LOX dependent fibroblast proliferation. Furthermore, morphological analysis demonstrates that platelets bind to the extracellular matrix component HA through its receptor CD44 and thereby induce a FAK dependent ASMC proliferation. Taken together, the results obtained in this thesis suggest that platelet/HA interaction mediated through CD44 is of importance for platelets ability to induce cell proliferation. Moreover, the results propose that platelet-induced fibroblast proliferation is 5-LOX dependent and that platelets induce a HA, CD44, FAK, 5-LOX, and ROSdependent ASMC proliferation. This action of platelets represents a potential important and novel mechanism that may have an impact on the remodeling process and in the development of new pharmacological strategies in the treatment of inflammatory respiratory disease such as asthma.

Place, publisher, year, edition, pages
Linköping: Linköping University Electronic Press, 2010. p. 80
Series
Linköping University Medical Dissertations, ISSN 0345-0082 ; 1203
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-61623 (URN)978-91-7393-324-7 (ISBN)
Public defence
2010-12-03, Berzeliussalen, Universitetssjukhuset, Campus US, Linköpings universitet, Linköping, 13:00 (Swedish)
Opponent
Supervisors
Available from: 2010-11-17 Created: 2010-11-17 Last updated: 2012-01-30Bibliographically approved
Svensson Holm, A.-C. B., Bengtsson, T., Grenegård, M. & Lindström, E. G. (2008). Platelets bind to hyaluronic acid through CD44 and induce a focal adhesion kinase dependent airway smooth muscle cell proliferation. , 19(7)
Open this publication in new window or tab >>Platelets bind to hyaluronic acid through CD44 and induce a focal adhesion kinase dependent airway smooth muscle cell proliferation
2008 (English)Manuscript (preprint) (Other academic)
Abstract [en]

Platelets have been implicated as important players in the remodeling process, e.g. due to their ability to induce airway smooth muscle cell (ASMC) proliferation. The aim of the present study was to investigate the role of the extracellular matrix component hyaluronic acid (HA), the HA-binding surface receptor CD44 and focal adhesion kinase (FAK) in platelet-induced ASMC proliferation. The ability of ASMC to synthesize HA was investigated by fluorescent staining using biotinylated HA-binding protein and streptavidin conjugate. In addition, the interaction between ASMC and platelets was studied by fluorescent staining of the F-actin. We found that ASMC produced HA and that a CD44 blocking antibody and the hyaluronic acid synthase inhibitor 4-Methylumbelliferone (4-MU) inhibited platelet binding to the area surrounding the ASMC. Proliferation of ASMC was measured using the MTS-assay, and we found that the CD44 blocking antibody and 4-MU inhibited platelet-induced ASMC proliferation. We also found that co-culture of ASMC and platelets resulted in increased phosphorylation of FAK as detected by Western blot analysis. Furthermore, the FAKinhibitor PF 573228 inhibited platelet-induced ASMC proliferation. In conclusion, our findings demonstrate that HA, CD44 and FAK contribute to the increased ASMC proliferation caused by platelets. This event is initiated by an interaction between platelets CD44 and HA produced by the ASMC. These new findings may be important in understanding the interplay between ECM, platelets and ASMC in the remodeling process. In conclusion, our results demonstrate that FAK is phosphorylated and on that account activated during the CD44-dependent platelet/ASMC interaction and this contributes to proliferation of the ASMC. These new findings may be important in understanding the interplay between ECM, platelets and ASMC in the remodeling process.

Keywords
airway smooth muscle; airway remodeling, hyaluronic acid, CD44, focal adhesion kinase
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-61622 (URN)
Available from: 2010-11-17 Created: 2010-11-17 Last updated: 2010-11-17Bibliographically approved
Svensson Holm, A.-C. B. ., Bengtsson, T., Grenegård, M. & Lindström, E. G. . (2008). Platelets stimulate airway smooth muscle cell proliferation through mechanisms involving 5-lipoxygenase and reactive oxygen species. Platelets, 19(7), 528-536
Open this publication in new window or tab >>Platelets stimulate airway smooth muscle cell proliferation through mechanisms involving 5-lipoxygenase and reactive oxygen species
2008 (English)In: Platelets, ISSN 0953-7104, E-ISSN 1369-1635, Vol. 19, no 7, p. 528-536Article in journal (Refereed) Published
Abstract [en]

Continuous recruitment and inappropriate activity of platelets in the airways may contribute to airway remodeling, a characteristic feature of inflammatory airway diseases that includes increased proliferation of the smooth muscle.

The aim of the present investigation was to examine the effect of platelets on proliferation of airway smooth muscle cells (ASMC) in culture and to determine the possible role of 5-lipoxygenase (5-LOX) and reactive oxygen species (ROS) in this context.

ASMC obtained from guinea pigs were cultured and co-incubated with washed platelets for 24 hours. Thereafter, the proliferation was measured with the MTS-assay, the results were also verified by using thymidine incorporation, DNA measurements and manual counting. The interaction between platelets and ASMC was visualised with fluorescence microscopy.

We found that platelets bind to the ASMC and the presence of platelets caused a significant dose-dependent increase in ASMC proliferation. Co-incubation of ASMC with platelets also increased ROS-production, detected by the fluorescent probe DCFDA. Furthermore, the platelet-induced proliferation was reduced in the presence of the NADPH-oxidase inhibitors DPI and apocynin.

A possible role of 5-LOX in platelet-induced proliferation and ROS-generation was evaluated by using the 5-LOX inhibitor AA-861 and the PLA2-inhibitor ATK. The results showed that inhibition of these enzymes significantly reduced the platelet-induced proliferation. Moreover, Western blot analysis revealed that the ASMC but not the platelets express 5-LOX.

In addition, our experiments revealed that the presence of AA-861 and ATK significantly inhibited the ROS-production generated upon coincubation of platelets and ASMC.

In conclusion, we show that platelets have a marked capacity to induce ASMC proliferation. Furthermore, our study indicates that the interaction between platelets and ASMC leads to activation of 5-LOX in the ASMC followed by an increased ROS-production, events resulting in enhanced ASMC proliferation. The new findings are of importance in understanding possible mechanisms contributing to airway remodeling.

Keywords
platelet-induced proliferation, airway smooth muscle, 5-lipoxygenase, reactive oxygen species, airway remodeling
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-15607 (URN)10.1080/09537100802320300 (DOI)
Note
Original publication: Ann-Charlotte B. Svensson Holm, Torbjörn Bengtsson, Magnus Grenegård and Eva G. Lindström, Platelets stimulate airway smooth muscle cell proliferation through mechanisms involving 5-lipoxygenase and reactive oxygen species, 2008, Platelets, (19), 7, 528-536.http://dx.doi.org/10.1080/09537100802320300. Copyright © Taylor & Francis Group, an informa businessAvailable from: 2008-11-20 Created: 2008-11-20 Last updated: 2017-12-14Bibliographically approved
Svensson, A.-C. B., Bengtsson, T., Grenegård, M., Söderström, M. & Lindström, E. G. (2007). Platelet fragments, like platelets, induce airway smooth muscle cell proliferation through mechanisms dependent on ros and 5-lox. Paper presented at EAS Helsinki.
Open this publication in new window or tab >>Platelet fragments, like platelets, induce airway smooth muscle cell proliferation through mechanisms dependent on ros and 5-lox
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2007 (English)Conference paper, Published paper (Refereed)
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-69418 (URN)
Conference
EAS Helsinki
Available from: 2011-06-27 Created: 2011-06-27 Last updated: 2013-10-23
Svensson, A.-C. B., Bengtsson, T., Grenegård, M. & Lindström, E. G. (2007). Platelet-induced 5-LOX activity is associated with ROS-dependent ASMC proliferation. Paper presented at ERS Stockholm.
Open this publication in new window or tab >>Platelet-induced 5-LOX activity is associated with ROS-dependent ASMC proliferation
2007 (English)Conference paper, Published paper (Refereed)
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-69419 (URN)
Conference
ERS Stockholm
Available from: 2011-06-27 Created: 2011-06-27 Last updated: 2011-07-01
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