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Grenegård, Magnus
Publications (10 of 19) Show all publications
Lunde, N. N., Gregersen, I., Ueland, T., Shetelig, C., Holm, S., Kong, X. Y., . . . Halvorsen, B. (2020). Legumain is upregulated in acute cardiovascular events and associated with improved outcome - potentially related to anti-inflammatory effects on macrophages. Atherosclerosis, 296, 74-82
Open this publication in new window or tab >>Legumain is upregulated in acute cardiovascular events and associated with improved outcome - potentially related to anti-inflammatory effects on macrophages
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2020 (English)In: Atherosclerosis, ISSN 0021-9150, E-ISSN 1879-1484, Vol. 296, p. 74-82Article in journal (Refereed) Published
Abstract [en]

Background and aims: We have previously found increased levels of the cysteine protease legumain in plasma and plaques from patients with carotid atherosclerosis. This study further investigated legumain during acute cardiovascular events.

Methods: Circulating levels of legumain from patients and legumain released from platelets were assessed by enzyme-linked-immunosorbent assay. Quantitative PCR and immunoblotting were used to study expression, while localization was visualized by immunohistochemistry.

Results: In the SUMMIT Malmo cohort (n = 339 with or without type 2 diabetes and/or cardiovascular disease [CVD], and 64 healthy controls), the levels of circulating legumain were associated with the presence of CVD in non-diabetics, with no relation to outcome. In symptomatic carotid plaques and in samples from both coronary and intracerebral thrombi obtained during acute cardiovascular events, legumain was co-localized with macrophages in the same regions as platelets. In vitro, legumain was shown to be present in and released from platelets upon activation. In addition, THP-1 macrophages exposed to releasate from activated platelets showed increased legumain expression. Interestingly, primary peripheral blood mononuclear cells stimulated with recombinant legumain promoted anti-inflammatory responses. Finally, in a STEMI population (POSTEMI; n = 272), patients had significantly higher circulating legumain before and immediately after percutaneous coronary intervention compared with healthy controls (n = 67), and high levels were associated with improved outcome.

Conclusions: Our data demonstrate for the first time that legumain is upregulated during acute cardiovascular events and is associated with improved outcome.

Place, publisher, year, edition, pages
Elsevier, 2020
Keywords
Cardiovascular disease, Legumain, Macrophage, Plaque modification, Platelets, Protease
National Category
Cardiac and Cardiovascular Systems
Identifiers
urn:nbn:se:oru:diva-80851 (URN)10.1016/j.atherosclerosis.2019.12.008 (DOI)000518470200014 ()31870625 (PubMedID)2-s2.0-85076845246 (Scopus ID)
Funder
Swedish Heart Lung FoundationSwedish Research CouncilSwedish Diabetes Association
Note

Funding Agencies:

University of Oslo  

South-Eastern Norway Regional Health Authority 2018084

Research Council of Norway 144139

Anders Jahres foundation for the Promotion of Science  

UNIFOR  

Blix foundation  Innovative Medicines Initiative (SUMMIT Consortium) IMI-2008/115006

Skåne University Hospital Foundations  

Region Skåne Grants  

Swedish Stroke Foundation 

Nansen foundation 

Available from: 2020-03-26 Created: 2020-03-26 Last updated: 2020-03-26Bibliographically approved
Kardeby, C., Paramel Varghese, G., Pournara, D., Fotopoulou, T., Sirsjö, A., Koufaki, M., . . . Grenegård, M. (2019). A novel purine analogue bearing nitrate ester prevents platelet activation by ROCK activity inhibition. European Journal of Pharmacology, 857, Article ID 172428.
Open this publication in new window or tab >>A novel purine analogue bearing nitrate ester prevents platelet activation by ROCK activity inhibition
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2019 (English)In: European Journal of Pharmacology, ISSN 0014-2999, E-ISSN 1879-0712, Vol. 857, article id 172428Article in journal (Refereed) Published
Abstract [en]

Natural purines like ATP, ADP and adenosine have crucial roles in platelet physiology. This knowledge has been significant in drug development and today ADP receptor antagonists are widely used for prevention of thrombotic events following myocardial infarction and ischaemic stroke.

Recent studies have shown that a purine analogue bearing nitrate ester group (denoted MK128) has anti-inflammatory effects probably due to its ability to donate nitric oxide (NO). However, other pharmacological mechanisms may contribute to the observed effect. The aim of the present study was to establish the anti-platelet activity and elucidate the underlying molecular mechanism(s) of the purine analogue MK128.

We found that MK128 reduced aggregation and secretion induced by the thrombin receptor agonist SFLLRN and nearly abolished aggregation and secretion induced by thromboxane A2 (TxA2) and collagen receptor agonists. The inhibition took place despite blockage of the NO/cGMP signalling system. Furthermore, interaction between MK128 and platelet purinergic receptors did not explain the observed inhibition. Instead, we found that MK128 concentration-dependently inhibited Rho-associated kinase (ROCK), which led to decreased ROCK-dependent myosin phosphatase target subunit (MYPT)-1 phosphorylation and suppression of platelet functional responses.

Place, publisher, year, edition, pages
Elsevier, 2019
Keywords
Nitric oxide, Platelet inhibitor, Purinergic receptors, Rho associated protein kinase, Thromboxane A2
National Category
Pharmacology and Toxicology
Identifiers
urn:nbn:se:oru:diva-74650 (URN)10.1016/j.ejphar.2019.172428 (DOI)000472711200011 ()31175850 (PubMedID)2-s2.0-85066786586 (Scopus ID)
Funder
Knowledge Foundation
Note

Funding Agency:

Onassis Foundation

Available from: 2019-06-10 Created: 2019-06-10 Last updated: 2019-11-14Bibliographically approved
Fälker, K., Ljungberg, L., Kardeby, C., Lindkvist, M., Sirsjö, A. & Grenegård, M. (2019). Adrenoceptor α2A signalling countervails the taming effects of synchronous cyclic nucleotide-elevation on thrombin-induced human platelet activation and aggregation. Cellular Signalling, 59, 96-109
Open this publication in new window or tab >>Adrenoceptor α2A signalling countervails the taming effects of synchronous cyclic nucleotide-elevation on thrombin-induced human platelet activation and aggregation
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2019 (English)In: Cellular Signalling, ISSN 0898-6568, E-ISSN 1873-3913, Vol. 59, p. 96-109Article in journal (Refereed) Published
Abstract [en]

The healthy vascular endothelium constantly releases autacoids which cause an increase of intracellular cyclic nucleotides to tame platelets from inappropriate activation. Elevating cGMP and cAMP, in line with previous reports, cooperated in the inhibition of isolated human platelet intracellular calcium-mobilization, dense granules secretion, and aggregation provoked by thrombin. Further, platelet alpha granules secretion and, most relevant, integrin αIIaβ3 activation in response to thrombin are shown to be prominently affected by the combined elevation of cGMP and cAMP. Since stress-related sympathetic nervous activity is associated with an increase in thrombotic events, we investigated the impact of epinephrine in this setting. We found that the assessed signalling events and functional consequences were to various extents restored by epinephrine, resulting in full and sustained aggregation of isolated platelets. The restoring effects of epinephrine were abolished by either interfering with intracellular calcium-elevation or with PI3-K signalling. Finally, we show that in our experimental setting epinephrine likewise reconstitutes platelet aggregation in heparinized whole blood, which may indicate that this mechanism could also apply in vivo.

Place, publisher, year, edition, pages
Elsevier, 2019
Keywords
Cyclic nucleotide, Epinephrine, Human platelets, Nitric oxide, Prostacyclin, α(2A) adrenoceptor
National Category
Physiology Cell and Molecular Biology
Identifiers
urn:nbn:se:oru:diva-73421 (URN)10.1016/j.cellsig.2019.03.019 (DOI)000468251000010 ()30926386 (PubMedID)2-s2.0-85063486315 (Scopus ID)
Funder
AFA Insurance, 130275Knowledge Foundation, 20150240
Available from: 2019-04-04 Created: 2019-04-04 Last updated: 2019-06-19Bibliographically approved
Befekadu, R., Christiansen, K., Larsson, A. & Grenegård, M. (2019). Increased plasma cathepsin S and trombospondin-1 in patients with acute ST-segment elevation myocardial infarction. Cardiology Journal, 26(4), 385-393
Open this publication in new window or tab >>Increased plasma cathepsin S and trombospondin-1 in patients with acute ST-segment elevation myocardial infarction
2019 (English)In: Cardiology Journal, ISSN 1897-5593, Vol. 26, no 4, p. 385-393Article in journal (Refereed) Published
Abstract [en]

Background: The role of cathepsins in the pathological progression of atherosclerotic lesions in ischemic heart disease have been defined in detail more than numerous times. This investigation examined the platelet-specific biomarker trombospondin-1 (TSP-1) and platelet function ex vivo, and compared this with cathepsin S (Cat-S; a biomarker unrelated to platelet activation but also associated this with increased mortality risk) in patients with ST-segment elevation myocardial infarction (STEMI).

Methods: The STEMI patients were divided into two groups depending on the degree of coronary vessel occlusion: those with closed (n = 90) and open culprit vessel (n = 40). Cat-S and TSP-1 were analyzed before, 1-3 days after and 3 months after percutanous coronary intervention (PCI).

Results: During acute STEMI, plasma TSP-1 was significantly elevated in patients with closed culprit lesions, but rapidly declined after PCI. In fact, TSP-1 after PCI was significantly lower inpatient samples compared to healthy individuals. In comparison, plasma Cat-S was significantly elevated both before and after PCI. In patients with closed culprit lesions, Cat-S was significantly higher compared to patients with open culprit lesions 3 months after PCI. Although troponin-I were higher (p < 0.01) in patients with closed culprit lesion, there was no correlation with Cat-S and TSP-1.

Conclusions: Cat-S but not TSP-1 may be a useful risk biomarker in relation to the severity of STEMI. However, the causality of Cat-S as a predictor for long-term mortality in STEMI remains to be ascertained in future studies.

Place, publisher, year, edition, pages
Via Medica, 2019
Keywords
ST-segment elevation myocardial infarction, cathepsin S, percutaneous coronary intervention, platelets
National Category
Cardiac and Cardiovascular Systems
Identifiers
urn:nbn:se:oru:diva-76449 (URN)10.5603/CJ.a2018.0030 (DOI)000483031700010 ()29611169 (PubMedID)2-s2.0-85071630437 (Scopus ID)
Note

Funding Agency:

Örebro University Hospital Research Foundation AFA Insurance 

Available from: 2019-09-16 Created: 2019-09-16 Last updated: 2019-09-16Bibliographically approved
Lindkvist, M., Fernberg, U., Ljungberg, L., Fälker, K., Fernström, M., Hurtig-Wennlöf, A. & Grenegård, M. (2019). Individual variations in platelet reactivity towards ADP, epinephrine, collagen and nitric oxide, and the association to arterial function in young, healthy adults. Thrombosis Research, 174, 5-12
Open this publication in new window or tab >>Individual variations in platelet reactivity towards ADP, epinephrine, collagen and nitric oxide, and the association to arterial function in young, healthy adults
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2019 (English)In: Thrombosis Research, ISSN 0049-3848, E-ISSN 1879-2472, Vol. 174, p. 5-12Article in journal (Refereed) Published
Abstract [en]

INTRODUCTION: Platelet aggregation and secretion can be induced by a large number of endogenous activators, such as collagen, adenosine diphosphate (ADP) and epinephrine. Conversely, the blood vessel endothelium constitutively release platelet inhibitors including nitric oxide (NO) and prostacyclin. NO and prostacyclin are also well-known vasodilators and contribute to alterations in local blood flow and systemic blood pressure.

MATERIALS AND METHODS: In this study we investigated individual variations in platelet reactivity and arterial functions including blood pressure and flow-mediated vasodilation (FMD) in 43 young, healthy individuals participating in the Lifestyle, Biomarkers and Atherosclerosis (LBA) study. Platelet aggregation and dense granule secretion were measured simultaneously by light transmission and luminescence. FMD was measured with ultrasound.

RESULTS: The platelet function assay showed inter-individual differences in platelet reactivity. Specifically, a sub-group of individuals had platelets with an increased response to low concentrations of ADP and epinephrine, but not collagen. When the NO-donor S-nitroso-N-acetyl-DL-penicillamine (SNAP) was combined with high doses of these platelet activators, the results indicated for sub-groups of NO-sensitive and NO-insensitive platelets. The individuals with NO-sensitive platelets in response to SNAP in combination with collagen had a higher capacity of FMD of the arteria brachialis.

CONCLUSIONS: Platelet reactivity towards ADP, epinephrine and NO differs between young, healthy individuals. Some individuals have a more effective response towards NO, both in the aspect of platelet inhibition ex vivo, as well as vasodilation in vivo.

Place, publisher, year, edition, pages
Elsevier, 2019
Keywords
Adenosine diphosphate, Collagen, Epinephrine, Nitric oxide, Platelet activation, Vasodilation
National Category
Physiology Hematology Cardiac and Cardiovascular Systems
Identifiers
urn:nbn:se:oru:diva-70787 (URN)10.1016/j.thromres.2018.12.008 (DOI)000456949100002 ()30543988 (PubMedID)2-s2.0-85058021347 (Scopus ID)
Funder
AFA Insurance, 130275Knowledge Foundation
Available from: 2018-12-18 Created: 2018-12-18 Last updated: 2019-03-26Bibliographically approved
Kardeby, C., Fälker, K., Haining, E. J., Criel, M., Lindkvist, M., Barroso, R., . . . Grenegård, M. (2019). Synthetic glycopolymers and natural fucoidans cause human platelet aggregation via PEAR1 and GPIbα. Blood advances, 3(3), 275-287
Open this publication in new window or tab >>Synthetic glycopolymers and natural fucoidans cause human platelet aggregation via PEAR1 and GPIbα
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2019 (English)In: Blood advances, ISSN 2473-9529, Vol. 3, no 3, p. 275-287Article in journal (Refereed) Published
Abstract [en]

Fucoidans are sulfated fucose-based polysaccharides that activate platelets and have pro- and anticoagulant effects; thus, they may have therapeutic value. In the present study, we show that 2 synthetic sulfated α-l-fucoside-pendant glycopolymers (with average monomeric units of 13 and 329) and natural fucoidans activate human platelets through a Src- and phosphatidylinositol 3-kinase (PI3K)-dependent and Syk-independent signaling cascade downstream of the platelet endothelial aggregation receptor 1 (PEAR1). Synthetic glycopolymers and natural fucoidan stimulate marked phosphorylation of PEAR1 and Akt, but not Syk. Platelet aggregation and Akt phosphorylation induced by natural fucoidan and synthetic glycopolymers are blocked by a monoclonal antibody to PEAR1. Direct binding of sulfated glycopolymers to epidermal like growth factor (EGF)-like repeat 13 of PEAR1 was shown by avidity-based extracellular protein interaction screen technology. In contrast, synthetic glycopolymers and natural fucoidans activate mouse platelets through a Src- and Syk-dependent pathway regulated by C-type lectin-like receptor 2 (CLEC-2) with only a minor role for PEAR1. Mouse platelets lacking the extracellular domain of GPIbα and human platelets treated with GPIbα-blocking antibodies display a reduced aggregation response to synthetic glycopolymers. We found that synthetic sulfated glycopolymers bind directly to GPIbα, substantiating that GPIbα facilitates the interaction of synthetic glycopolymers with CLEC-2 or PEAR1. Our results establish PEAR1 as the major signaling receptor for natural fucose-based polysaccharides and synthetic glycopolymers in human, but not in mouse, platelets. Sulfated α-l-fucoside-pendant glycopolymers are unique tools for further investigation of the physiological role of PEAR1 in platelets and beyond.

Place, publisher, year, edition, pages
American Society of Hematology, 2019
National Category
Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy) Hematology
Identifiers
urn:nbn:se:oru:diva-72478 (URN)10.1182/bloodadvances.2018024950 (DOI)000458442500007 ()30700416 (PubMedID)2-s2.0-85060943358 (Scopus ID)
Funder
Knowledge Foundation
Note

Funding Agencies:

BHF  PG/16/53/32242  RG/13/18/30563 

Deutsche Forschungsgemeinschaft  DFG: Eb 177/14-1 

Fonds voor Wetenschappelijk Onderzoek Vlaanderen grant  G0A6514N 

Available from: 2019-02-14 Created: 2019-02-14 Last updated: 2019-06-18Bibliographically approved
Zegeye, M. M., Lindkvist, M., Fälker, K., Kumawat, A. K., Paramel Varghese, G., Grenegård, M., . . . Ljungberg, L. U. (2018). Activation of the JAK/STAT3 and PI3K/AKT pathways are crucial for IL-6 trans-signaling-mediated pro-inflammatory response in human vascular endothelial cells. Cell Communication and Signaling, 16(1), Article ID 55.
Open this publication in new window or tab >>Activation of the JAK/STAT3 and PI3K/AKT pathways are crucial for IL-6 trans-signaling-mediated pro-inflammatory response in human vascular endothelial cells
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2018 (English)In: Cell Communication and Signaling, ISSN 1478-811X, E-ISSN 1478-811X, Vol. 16, no 1, article id 55Article in journal (Refereed) Published
Abstract [en]

BACKGROUND: IL-6 classic signaling is linked to anti-inflammatory functions while the trans-signaling is associated with pro-inflammatory responses. Classic signaling is induced via membrane-bound IL-6 receptor (IL-6R) whereas trans-signaling requires prior binding of IL-6 to the soluble IL-6R. In both cases, association with the signal transducing gp130 receptor is compulsory. However, differences in the downstream signaling mechanisms of IL-6 classic- versus trans-signaling remains largely elusive.

METHODS: In this study, we used flow cytometry, quantitative PCR, ELISA and immuno-blotting techniques to investigate IL-6 classic and trans-signaling mechanisms in Human Umbilical Vein Endothelial Cells (HUVECs).

RESULTS: We show that both IL-6R and gp130 are expressed on the surface of human vascular endothelial cells, and that the expression is affected by pro-inflammatory stimuli. In contrast to IL-6 classic signaling, IL-6 trans-signaling induces the release of the pro-inflammatory chemokine Monocyte Chemoattractant Protein-1 (MCP-1) from human vascular endothelial cells. In addition, we reveal that the classic signaling induces activation of the JAK/STAT3 pathway while trans-signaling also activates the PI3K/AKT and the MEK/ERK pathways. Furthermore, we demonstrate that MCP-1 induction by IL-6 trans-signaling requires simultaneous activation of the JAK/STAT3 and PI3K/AKT pathways.

CONCLUSIONS: Collectively, our study reports molecular differences in IL-6 classic- and trans-signaling in human vascular endothelial cells; and elucidates the pathways which mediate MCP-1 induction by IL-6 trans-signaling.

Place, publisher, year, edition, pages
BioMed Central, 2018
Keywords
Endothelium, HUVECs, Interleukin-6 signaling, Monocyte chemoattractant Protein-1, Pro-inflammatory cytokines
National Category
Cell and Molecular Biology
Research subject
Physical Education and Sport Pedagogy; Physical Education and Sport Pedagogy
Identifiers
urn:nbn:se:oru:diva-68803 (URN)10.1186/s12964-018-0268-4 (DOI)000443839900001 ()30185178 (PubMedID)2-s2.0-85053157310 (Scopus ID)
Funder
Knowledge Foundation
Note

Funding Agencies:

Längmanska Foundation  

Foundation for Old Servants (Stiftelsen Gamla Tjänarinnor)  

Available from: 2018-09-10 Created: 2018-09-10 Last updated: 2019-03-26Bibliographically approved
Tengdelius, M., Kardeby, C., Fälker, K., Griffith, M., Påhlsson, P., Konradsson, P. & Grenegård, M. (2017). Fucoidan-Mimetic Glycopolymers as Tools for Studying Molecular and Cellular Responses in Human Blood Platelets. Macromolecular Bioscience, 17(2), Article ID UNSP 1600257.
Open this publication in new window or tab >>Fucoidan-Mimetic Glycopolymers as Tools for Studying Molecular and Cellular Responses in Human Blood Platelets
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2017 (English)In: Macromolecular Bioscience, ISSN 1616-5187, E-ISSN 1616-5195, Vol. 17, no 2, article id UNSP 1600257Article in journal (Refereed) Published
Abstract [en]

The marine sulfated polysaccharide fucoidan displays superior ability to induce platelet aggregation compared to other sulfated polysaccharides. As such, it is an attractive tool for studying molecular and cellular responses in activated platelets. The heterogeneous structure, however, poses a problem in such applications. This study describes the synthesis of sulfated α-l-fucoside-pendant poly(methacryl amides) with homogeneous structures. By using both thiol-mediated chain transfer and reversible addition-fragmentation chain transfer polymerization techniques, glycopolymers with different chain lengths are obtained. These glycopolymers show platelet aggregation response and surface changes similar to those of fucoidan, and cause platelet activation through intracellular signaling as shown by extensive protein tyrosine phosphorylation. As the platelet activating properties of the glycopolymers strongly mimic those of fucoidan, this study concludes these fucoidan-mimetic glycopolymers are unique tools for studying molecular and cellular responses in human blood platelets.

Place, publisher, year, edition, pages
Weinheim, Germany: Wiley-VCH Verlagsgesellschaft, 2017
Keywords
biological applications of polymers; biomimetic; radical polymerization; reversible addition fragmentation chain transfer; structure-property relations
National Category
Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy)
Identifiers
urn:nbn:se:oru:diva-52179 (URN)10.1002/mabi.201600257 (DOI)000394592600012 ()27616165 (PubMedID)2-s2.0-84987653303 (Scopus ID)
Note

Funding Agency:

AFA Insurance, VR Treatments of the Future grant

Available from: 2016-09-21 Created: 2016-09-14 Last updated: 2019-05-06Bibliographically approved
Donner, L., Fälker, K., Gremer, L., Klinker, S., Pagani, G., Ljungberg, L. U., . . . Elvers, M. (2016). Platelets contribute to amyloid-β aggregation in cerebral vessels through integrin αIIbβ3-induced outside-in signaling and clusterin release. Science Signaling, 9(429), Article ID ra52.
Open this publication in new window or tab >>Platelets contribute to amyloid-β aggregation in cerebral vessels through integrin αIIbβ3-induced outside-in signaling and clusterin release
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2016 (English)In: Science Signaling, ISSN 1945-0877, E-ISSN 1937-9145, Vol. 9, no 429, article id ra52Article in journal (Refereed) Published
Abstract [en]

Cerebral amyloid angiopathy (CAA) is a vascular dysfunction disorder characterized by deposits of amyloid-β (Aβ) in the walls of cerebral vessels. CAA and Aβ deposition in the brain parenchyma contribute to dementia and Alzheimer's disease (AD). We investigated the contribution of platelets, which accumulate at vascular Aβ deposits, to CAA. We found that synthetic monomeric Aβ40 bound through its RHDS (Arg-His-Asp-Ser) sequence to integrin αIIbβ3, which is the receptor for the extracellular matrix protein fibrinogen, and stimulated the secretion of adenosine diphosphate (ADP) and the chaperone protein clusterin from platelets. Clusterin promoted the formation of fibrillar Aβ aggregates, and ADP acted through its receptors P2Y1 and P2Y12 on platelets to enhance integrin αIIbβ3 activation, further increasing the secretion of clusterin and Aβ40 binding to platelets. Platelets from patients with Glanzmann's thrombasthenia, a bleeding disorder in which platelets have little or dysfunctional αIIbβ3, indicated that the abundance of this integrin dictated Aβ-induced clusterin release and platelet-induced Aβ aggregation. The antiplatelet agent clopidogrel, which irreversibly inhibits P2Y12, inhibited Aβ aggregation in platelet cultures; in transgenic AD model mice, this drug reduced the amount of clusterin in the circulation and the incidence of CAA. Our findings indicate that activated platelets directly contribute to CAA by promoting the formation of Aβ aggregates and that Aβ, in turn, activates platelets, creating a feed-forward loop. Thus, antiplatelet therapy may alleviate fibril formation in cerebral vessels of AD patients.

Place, publisher, year, edition, pages
Washington, USA: American Association for the Advancement of Science (A A A S), 2016
National Category
Cell Biology
Research subject
Cell Research
Identifiers
urn:nbn:se:oru:diva-50493 (URN)10.1126/scisignal.aaf6240 (DOI)000376467800003 ()27221710 (PubMedID)2-s2.0-84971265417 (Scopus ID)
Note

Funding Agency:

Julich Supercomputing Center HDD11

Available from: 2016-05-31 Created: 2016-05-30 Last updated: 2019-03-26Bibliographically approved
Sodergren, A. L., Holm, A.-C. B. S., Ramström, S., Lindström, E. G., 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, 2016
Keywords
ADP receptors, endothelium, exocytosis, lysosome, platelet physiology, protease activated receptors (PAR), thrombin
National Category
Hematology
Identifiers
urn:nbn:se:oru:diva-48481 (URN)10.3109/09537104.2015.1042446 (DOI)000368717700011 ()25970449 (PubMedID)2-s2.0-84955347294 (Scopus ID)
Funder
Swedish Research Council
Note

Funding Agency:

County Council of Östergötland

Available from: 2016-02-23 Created: 2016-02-23 Last updated: 2019-03-26Bibliographically approved
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