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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
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
Fälker, K., Klarström-Engström, K., Bengtsson, T., Lindahl, T. L. & Grenegård, M. (2014). The Toll-like receptor 2/1 (TLR2/1) complex initiates human platelet activation via the src/Syk/LAT/PLC gamma 2 signalling cascade. Cellular Signalling, 26(2), 279-286
Open this publication in new window or tab >>The Toll-like receptor 2/1 (TLR2/1) complex initiates human platelet activation via the src/Syk/LAT/PLC gamma 2 signalling cascade
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2014 (English)In: Cellular Signalling, ISSN 0898-6568, E-ISSN 1873-3913, Vol. 26, no 2, p. 279-286Article in journal (Refereed) Published
Abstract [en]

The specific TLR2/1 complex activator Pam3CSK4 has been shown to provoke prominent activation and aggregation of human non-nucleated platelets. As Pam3CSK4-evoked platelet activation does not employ the major signalling pathway established in nucleated immune cells, we investigated if the TLR2/1 complex on platelets may initiate signalling pathways known to be induced by physiological agonists such as collagen via GPVI or thrombin via PARs. We found that triggering TLR2/1 complex-signalling with Pam3CSK4, in common with that induced via GPVI, and in contrast to that provoked by PARS, involves tyrosine phosphorylation of the adaptor protein LAT as well as of PLC gamma 2 in a src- and Syk-dependent manner. In this respect, we provide evidence that Pam3CSK4 does not cross-activate GPVI. Further, by the use of platelets from a Glanzmann's thrombasthenia patient lacking beta(3), in contrast to findings in nucleated immune cells, we show that the initiation of platelet activation by Pam3CSK4 does not involve integrin beta(3) signalling; whereas the latter, subsequent to intermediate TXA2 synthesis and signalling, was found to be indispensable for proper dense granule secretion and full platelet aggregation. Together, our findings reveal that triggering the TLR2/1 complex with Pam3CSK4 initiates human platelet activation by engaging tyrosine kinases of the src family and Syk, the adaptor protein LAT, as well as the key mediator PLC gamma 2. (C) 2013 Elsevier Inc. All rights reserved.

Place, publisher, year, edition, pages
New York, USA: Elsevier, 2014
Keywords
Human platelets, TLR2, Pam3CSK4, Syk, LAT, PLC gamma 2
National Category
Medical and Health Sciences Cell Biology
Research subject
Cell Research
Identifiers
urn:nbn:se:oru:diva-34261 (URN)10.1016/j.cellsig.2013.11.011 (DOI)000330922800012 ()24240055 (PubMedID)2-s2.0-84889605890 (Scopus ID)
Funder
Swedish Research CouncilSwedish Heart Lung Foundation
Note

Funding Agencies:

Foundation of Olle Engkvist

Medical Faculty of the University of Linkoping through Forsknings- och Forskarutbildningsnamnden (FUN)

Available from: 2014-03-13 Created: 2014-03-13 Last updated: 2019-03-26Bibliographically approved
Fälker, K., Nazare, M., Wonerow, P. & Kozian, D. H. (2013). Targeting Platelet G Protein-Coupled Receptors for Antithrombotic Therapy. Drug development research (Print), 74(7), 440-449
Open this publication in new window or tab >>Targeting Platelet G Protein-Coupled Receptors for Antithrombotic Therapy
2013 (English)In: Drug development research (Print), ISSN 0272-4391, E-ISSN 1098-2299, Vol. 74, no 7, p. 440-449Article in journal (Refereed) Published
Abstract [en]

Platelets are small anucleated cells produced by bone marrow megakaryocytes that circulate in the blood as sentinels of vascular integrity. They play a pivotal role in the regulation of vascular homeostasis through adhesion to the injured vessel wall, aggregation, propagation of coagulation, and thrombus formation. Furthermore, platelets are also involved in fibrinolysis and the repair of the blood vessel wall, restoring blood flow and vascular integrity. Under pathophysiological conditions such as atherosclerosis, inappropriate platelet aggregation and clot formation can cause vascular occlusions, resulting in myocardial infarctions or stroke that, according to the World Health Organization, represent with more than 10% of worldwide death a major health risk (http://who.int/mediacentre/factsheets/fs310/en/). Over the last several decades, increasing efforts have been made to elucidate the cellular components, signaling pathways, and risk factors contributing to platelet activation with the main goal of providing a sound basis for the development of antiplatelet drugs and novel therapeutic treatment strategies. The family of seven transmembrane receptors, also designated G protein-coupled receptors (GPCRs), represented by approximately 800 members identified in the human genome represent the largest class of receptors and, hence, the richest source of targets for drug discovery. Here, we here provide an overview of the commonly applied therapies targeting platelet-GPCRs as well as a brief summary of novel approaches.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:oru:diva-32466 (URN)10.1002/ddr.21101 (DOI)000325858500006 ()
Available from: 2013-11-20 Created: 2013-11-20 Last updated: 2019-03-26Bibliographically approved
Elvers, M., Grenegård, M., Khoshjabinzadeh, H., Münzer, P., Borst, O., Tian, H., . . . Fälker, K. (2012). A novel role for phospholipase D as an endogenous negative regulator of platelet sensitivity. Cellular Signalling, 24(9), 1743-52
Open this publication in new window or tab >>A novel role for phospholipase D as an endogenous negative regulator of platelet sensitivity
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2012 (English)In: Cellular Signalling, ISSN 0898-6568, E-ISSN 1873-3913, Vol. 24, no 9, p. 1743-52Article in journal (Refereed) Published
Abstract [en]

Platelet aggregation, secretion and thrombus formation play a critical role in primary hemostasis to prevent excessive blood loss. On the other hand, uncontrolled platelet activation leads to pathological thrombus formation resulting in myocardial infarction or stroke. Stimulation of heterotrimeric G-proteins by soluble agonists or immunoreceptor tyrosine based activation motif-coupled receptors that interact with immobilized ligands such as the collagen receptor glycoprotein (GP) VI lead to the activation of phospholipases that cleave membrane phospholipids to generate soluble second messengers. Platelets contain the phospholipases (PL) D1 and D2 which catalyze the hydrolysis of phosphatidylcholine to generate the second messenger phosphatidic acid (PA). The production of PA is abrogated by primary alcohols that have been widely used for the analysis of PLD-mediated processes. However, it is not clear if primary alcohols effectively reduce PA generation or if they induce PLD-independent cellular effects. In the present study we made use of the specific PLD inhibitor 5-fluoro-2-indolyl des-chlorohalopemide (FIPI) and show for the first time, that FIPI enhances platelet dense granule secretion and aggregation of human platelets. Further, FIPI has no effect on cytosolic Ca(2+) activity but needs proper Rho kinase signaling to mediate FIPI-induced effects on platelet activation. Upon FIPI treatment the phosphorylation of the PKC substrate pleckstrin was prominently enhanced suggesting that FIPI affects PKC-mediated secretion and aggregation in platelets. Similar effects of FIPI were observed in platelets from mouse wild-type and Pld1(-/-) mice pointing to a new role for PLD2 as a negative regulator of platelet sensitivity.

Place, publisher, year, edition, pages
New York, USA: Elsevier, 2012
Keywords
PLD, platelets, secretion, aggregation, regulation
National Category
Pharmacology and Toxicology Cell and Molecular Biology
Identifiers
urn:nbn:se:oru:diva-42401 (URN)10.1016/j.cellsig.2012.04.018 (DOI)000306621000003 ()22579635 (PubMedID)2-s2.0-84862656303 (Scopus ID)
Available from: 2015-02-04 Created: 2015-02-04 Last updated: 2019-03-26Bibliographically approved
Osman, A. & Fälker, K. (2011). Characterization of human platelet microRNA by quantitative PCR coupled with an annotation network for predicted target genes. Platelets, 22(6), 433-41
Open this publication in new window or tab >>Characterization of human platelet microRNA by quantitative PCR coupled with an annotation network for predicted target genes
2011 (English)In: Platelets, ISSN 0953-7104, E-ISSN 1369-1635, Vol. 22, no 6, p. 433-41Article in journal (Refereed) Published
Abstract [en]

Platelets are anucleate blood cells that play a crucial role in thrombosis and hemostasis. Despite their lack of nuclear DNA, platelets contain significant amounts of microRNA (miRNA) that may have vital functions in post-transcriptional gene regulation. Here, we combined comprehensive miRNA expression profiling by quantitative PCR with target prediction analysis for the most abundant miRNAs in human platelets. A network composed of predicted platelet miRNA target genes was then constructed, using annotations available in Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) databases. In addition, we evaluated possible differences in miRNA levels between resting and thrombin-stimulated platelets. We identified 281 transcripts, including 228 mature miRNAs and 53 minor miRNAs (or miR*), of which six miRNAs (miR-15 a, miR-339-3 p, miR-365, miR-495, miR-98, and miR-361-3 p) were up- or down-regulated in activated human platelets (P ≤ 0.001). A redundancy-reduced network was established that encompassed 246 genes in five statistically significant functional clusters representing platelet miRNA regulating pathways. Comparison of the 246 network genes with the platelet mRNA expression data available at ArrayExpress database confirmed that most of these genes (89%) are expressed in human platelets. In conclusion, this work affirms a recent microarray study reporting a wide-spread existence of miRNAs in human platelets. Further, we observed that thrombin stimulation was associated with altered levels of some miRNAs in platelets. The proposed functional network, combining computational prediction analysis with annotations from experimental observations, may in addition provide some information about probable miRNA target pathways in human platelets.

Place, publisher, year, edition, pages
London, United Kingdom: Informa Healthcare, 2011
Keywords
Annotation network, gene expression, microRNA, platelets
National Category
Cell and Molecular Biology
Identifiers
urn:nbn:se:oru:diva-42399 (URN)10.3109/09537104.2011.560305 (DOI)000293600300005 ()21438667 (PubMedID)2-s2.0-80051523967 (Scopus ID)
Available from: 2015-02-04 Created: 2015-02-04 Last updated: 2019-03-26Bibliographically approved
Organisations
Identifiers
ORCID iD: ORCID iD iconorcid.org/0000-0003-2519-203x

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