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  • 1.
    Befekadu, Rahel
    et al.
    Örebro University, School of Medical Sciences. Department of Laboratory Medicine, Section for Transfusion Medicine.
    Christiansen, Kjeld
    Department of Cardiology, Örebro University Hospital, Örebro, Sweden.
    Larsson, Anders
    Department of Medical Sciences, Uppsala University, Uppsala, Sweden.
    Grenegård, Magnus
    Örebro University, School of Medical Sciences. Cardiovascular Research Centre.
    Increased plasma cathepsin S and trombospondin-1 in patients with acute ST-segment elevation myocardial infarction2019In: Cardiology Journal, ISSN 1897-5593, Vol. 26, no 4, p. 385-393Article in journal (Refereed)
    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.

  • 2.
    Befekadu, Rahel
    et al.
    Örebro University, School of Medical Sciences. Department of Laboratory Medicine, Section for Clinical Immunology and Transfusion medicine, Örebro University Hospital, Örebro, Sweden.
    Grenegård, Magnus
    Örebro University, School of Medical Sciences.
    Larsson, Anders
    Department of Medical Sciences, Uppsala University, Uppsala, Sweden.
    Christensen, Kjeld
    Karlstad Central Hospital, Karlstad, Sweden; Department of Cardiology, Örebro University Hospital, Örebro, Sweden.
    Nilsson, Bo
    Department of Immunology, Genetics and Pathology, Rudbeck Laboratory C5:3, Uppsala University, Uppsala, Sweden.
    Ramström, Sofia
    Örebro University, School of Medical Sciences. Department of Clinical Chemistry, and Department of Biomedical and Clinical Sciences, Linköping University, Linköping, Sweden.
    Activation of the lectin complement pathway during and after ST segment elevation myocardial infarctionManuscript (preprint) (Other academic)
  • 3.
    Befekadu, Rahel
    et al.
    Örebro University, School of Medical Sciences. Department of Laboratory Medicine, Section for Clinical Immunology and Transfusion Medicine, Örebro University Hospital, Örebro, Sweden.
    Grenegård, Magnus
    Örebro University, School of Medical Sciences.
    Larsson, Anders
    Department of Medical Sciences, Uppsala University, Uppsala, Sweden.
    Christensen, Kjeld
    Karlstad Central Hospital, Karlstad, Sweden.
    Ramström, Sofia
    Örebro University, School of Medical Sciences. Department of Clinical Chemistry, Department of Biomedical and Clinical Sciences, Linköping University, Linköping, Sweden.
    Dynamic Changes in Pentraxin-3 and Neprilysin in ST Segment Elevation Myocardial Infarction2022In: Biomedicines, E-ISSN 2227-9059, Vol. 10, no 2, article id 275Article in journal (Refereed)
    Abstract [en]

    Pentraxin-3 (PTX3) and neprilysin have been associated with increased morbidity and mortality in chronic inflammatory disease and heart failure, but these biomarkers have been studied less in patients with ST segment elevation myocardial infarction (STEMI). We investigated the dynamic changes in these biomarkers, as well as the well-known C-reactive protein (CRP), in STEMI patients. PTX3, neprilysin and CRP were measured in samples from 165 STEMI patients, collected at the acute stage, 1-3 days after and 3 months after percutaneous coronary intervention (PCI), and from 40 healthy donors. Patient survival was followed for approximately 8 years after the PCI. As compared with samples from healthy donors, plasma levels of CRP and PTX3 were significantly increased in the acute samples and 1-3 days after PCI, but not at 3 months. CRP levels peaked at 1-3 days, while PTX3 was similarly high in both acute and 1-3 days samples. For neprilysin, no significant differences were observed at the group level. We found no significant differences when comparing patients with patent versus occluded culprit vessels or between patients having a thrombus aspiration or not. However, we found a significant reduction in survival for individuals with PTX3 above the median, both for samples collected at the acute stage and 1-3 days after PCI (p = 0.0001 and p = 0.0008, respectively). For CRP, no significant differences were observed using this approach, but patients above the reference range for healthy donors in the acute samples showed significantly lower survival (p = 0.0476). Conclusions: Survival analysis suggests that PTX3 might be a promising marker to predict mortality in this patient population.

  • 4.
    Befekadu, Rahel
    et al.
    Örebro University, School of Medical Sciences. Department of Laboratory Medicine, Section for Clinical Immunology and Transfusion Medicine, Örebro University Hospital, Örebro, Sweden.
    Grenegård, Magnus
    Örebro University, School of Medical Sciences.
    Larsson, Anders
    Department of Medical Sciences, Uppsala University, Uppsala, Sweden.
    Christensen, Kjeld
    Karlstad Central Hospital, Karlstad, Sweden; Department of Cardiology, Örebro University Hospital, Örebro, Sweden.
    Ramström, Sofia
    Örebro University, School of Medical Sciences. Department of Clinical Chemistry, Department of Biomedical and Clinical Sciences, Linköping University, Linköping, Sweden.
    Levels of soluble tumor necrosis factor receptor 1 and 2 are associated with survival after ST segment elevation myocardial infarction2022In: Scientific Reports, E-ISSN 2045-2322, Vol. 12, no 1, article id 14762Article in journal (Refereed)
    Abstract [en]

    The soluble tumor necrosis factor receptors (sTNFR1 and sTNFR2) are suggested to play dual roles on physiological and pathophysiological actions of TNF-α. The aim of this study was to investigate the dynamic changes of these biomarkers in patients with ST-segment elevation myocardial infarction (STEMI). Blood was collected from 165 STEMI patients at admission, 1-3 days and 3 months after percutaneous coronary intervention (PCI) and from 40 healthy blood donors. sTNFR1 and sTNFR2 were measured with ELISA. The plasma levels of both sTNFR1 and sTNFR2 were significantly higher than in healthy donors at all three time points. We found no significant differences in sTNFR1 or sTNFR2 when comparing patients with patent versus occluded culprit vessels, or between patients having a thrombus aspiration or not. Survival analysis was performed comparing patients with levels of biomarkers above and below the median values at that time point. We found significant differences in survival for sTNFR2 in acute samples (p = 0.0151) and for both sTNFR1 and sTNFR2 in samples 1-3 days after PCI (p = 0.0054 and p = 0.0003, respectively). Survival analyses suggest that sTNFR1 or sTNFR2 could be promising markers to predict mortality in STEMI patients after PCI.

  • 5.
    Boknäs, Niklas
    et al.
    Department of Clinical and Experimental Medicine, Linköping University, Linköping, Sweden.
    Faxälv, Lars
    Department of Clinical and Experimental Medicine, Linköping University, Linköping, Sweden.
    Sanchez Cenellas, Daniel
    Department of Clinical and Experimental Medicine, Linköping University, Linköping, Sweden.
    Wallstedt, Maria
    Department of Clinical and Experimental Medicine, Linköping University, Linköping, Sweden.
    Ramström, Sofia
    Department of Clinical and Experimental Medicine, Linköping University, Linköping, Sweden.
    Grenegård, Magnus
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden.
    Lindahl, Tomas L.
    Department of Clinical and Experimental Medicine, Linköping University, Linköping, Sweden.
    Thrombin-induced platelet activation via PAR4: pivotal role for exosite II2014In: Thrombosis and Haemostasis, ISSN 0340-6245, E-ISSN 2567-689X, Vol. 112, no 3, p. 558-565Article in journal (Refereed)
    Abstract [en]

    Thrombin-induced platelet activation via PAR1 and PAR4 is an important event in haemostasis. Although the underlying mechanisms responsible for ensuring efficient PAR1 activation by thrombin have been extensively studied, the potential involvement of recognitions sites outside the active site of the protease in thrombin-induced PAR4 activation is largely unknown. In this study, we developed a new assay to assess the importance of exosite I and II for PAR4 activation with alpha- and gamma-thrombin. Surprisingly, we found that exosite II is critical for activation of PAR4. We also show that this dependency on exosite II likely represents a new mechanism, as it is unaffected by blockage of the previously known interaction between thrombin and glycoprotein Ib alpha.

  • 6.
    Donner, Lili
    et al.
    Department of Clinical and Experimental Hemostasis, Hemotherapy and Transfusion Medicine, Heinrich Heine University, Düsseldorf, Germany.
    Fälker, Knut
    Örebro University, School of Medical Sciences. Cardiovascular Research Centre, Örebro University Hospital, Örebro, Sweden.
    Gremer, Lothar
    Institute of Physical Biology, Heinrich Heine University, Düsseldorf, Germany; Institute of Structural Biochemistry (ICS-6), Research Centre Jülich, Jülich, Germany.
    Klinker, Stefan
    Institute of Physical Biology, Heinrich Heine University, Düsseldorf, Germany.
    Pagani, Giulia
    Institute for Pharmaceutical and Medicinal Chemistry, Department of Mathematics and Natural Sciences, Heinrich Heine University, Düsseldorf, Germany.
    Ljungberg, Liza U.
    Örebro University, School of Medical Sciences. Cardiovascular Research Centre, Örebro University Hospital, Örebro, Sweden.
    Lothmann, Kimberley
    Institute of Physical Biology, Heinrich Heine University, Düsseldorf, Germany.
    Rizzi, Federica
    Department of Biomedical, Biotechnological, and Translation Sciences, University of Parma, Parma, Italy; Centre for Molecular and Translational Oncology (COMT), University of Parma, Parma, Italy; National Institute of Biostructure and Biosystems (INBB), Rome, Italy.
    Schaller, Martin
    Department of Dermatology, University of Tübingen, Tübingen, Germany.
    Gohlke, Holger
    Institute for Pharmaceutical and Medicinal Chemistry, Department of Mathematics and Natural Sciences, Heinrich Heine University, Düsseldorf, Germany.
    Willbold, Dieter
    Institute of Physical Biology, Heinrich Heine University, Düsseldorf, Germany; Institute of Structural Biochemistry (ICS-6), Research Centre Jülich, Jülich, Germany.
    Grenegård, Magnus
    Örebro University, School of Medical Sciences. Cardiovascular Research Centre, Örebro University Hospital, Örebro, Sweden.
    Elvers, Margitta
    Department of Clinical and Experimental Hemostasis, Hemotherapy and Transfusion Medicine, Heinrich Heine University, Düsseldorf, Germany.
    Platelets contribute to amyloid-β aggregation in cerebral vessels through integrin αIIbβ3-induced outside-in signaling and clusterin release2016In: Science Signaling, ISSN 1945-0877, E-ISSN 1937-9145, Vol. 9, no 429, article id ra52Article in journal (Refereed)
    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.

  • 7.
    Elvers, Margitta
    et al.
    Medizinische Klinik III, Dept. of Cardiology and Cardiovascular Diseases, Eberhard Karls University, Tübingen, Germany.
    Grenegård, Magnus
    Faculty of Health Sciences, Department of Medicine and Health, Division of Drug Research/Pharmacology, University of Linköping, Linköping, Sweden.
    Khoshjabinzadeh, Hanieh
    Department of Clinical and Experimental Medicine, Division of Clinical Chemistry, University of Linköping, Linköping, Sweden.
    Münzer, Patrick
    Department of Physiology, Eberhard Karls University, Tübingen, Germany.
    Borst, Oliver
    Medizinische Klinik III, Dept. of Cardiology and Cardiovascular Diseases, Eberhard Karls University, Tübingen, Germany; Department of Physiology, Eberhard Karls University, Tübingen, Germany.
    Tian, Huasong
    Department of Pathology and Cell Biology, Taub Institute for Research on Alzheimer's Disease and the Aging Brain, Columbia University Medical Center, New York, USA.
    Di Paolo, Gilbert
    Department of Pathology and Cell Biology, Taub Institute for Research on Alzheimer's Disease and the Aging Brain, Columbia University Medical Center, New York, USA.
    Lang, Florian
    Department of Physiology, Eberhard Karls University, Tübingen, Germany.
    Gawaz, Meinrad
    Medizinische Klinik III, Dept. of Cardiology and Cardiovascular Diseases, Eberhard Karls University, Tübingen, Germany.
    Lindahl, Tomas L
    Department of Clinical and Experimental Medicine, Division of Clinical Chemistry, Linköping University, Linköping, Sweden.
    Fälker, Knut
    Department of Clinical and Experimental Medicine, Division of Clinical Chemistry, Linköping University, Linköping, Sweden.
    A novel role for phospholipase D as an endogenous negative regulator of platelet sensitivity2012In: Cellular Signalling, ISSN 0898-6568, E-ISSN 1873-3913, Vol. 24, no 9, p. 1743-52Article in journal (Refereed)
    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.

  • 8.
    Fälker, Knut
    et al.
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden. Department of Biomedicine; Dept Clin & Expt Med, Linköping Univ, Linköping, Sweden.
    Klarström-Engström, Kristin
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden. Department of Biomedicine.
    Bengtsson, Torbjörn
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden. Department of Biomedicine.
    Lindahl, Tomas L.
    Dept Clin & Expt Med, Linköping Univ, Linköping, Sweden.
    Grenegård, Magnus
    Örebro University, School of Medicine, Örebro University, Sweden. Department of Biomedicine.
    The Toll-like receptor 2/1 (TLR2/1) complex initiates human platelet activation via the src/Syk/LAT/PLC gamma 2 signalling cascade2014In: Cellular Signalling, ISSN 0898-6568, E-ISSN 1873-3913, Vol. 26, no 2, p. 279-286Article in journal (Refereed)
    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.

  • 9.
    Fälker, Knut
    et al.
    Örebro University, School of Medical Sciences. Cardiovascular Research Centre (CVRC).
    Ljungberg, Liza
    Örebro University, School of Medical Sciences. Cardiovascular Research Centre (CVRC).
    Kardeby, Caroline
    Örebro University, School of Medical Sciences. Cardiovascular Research Centre (CVRC).
    Lindkvist, Madelene
    Örebro University, School of Medical Sciences. Cardiovascular Research Centre (CVRC).
    Sirsjö, Allan
    Örebro University, School of Medical Sciences. Cardiovascular Research Centre (CVRC).
    Grenegård, Magnus
    Örebro University, School of Medical Sciences. Cardiovascular Research Centre (CVRC).
    Adrenoceptor α2A signalling countervails the taming effects of synchronous cyclic nucleotide-elevation on thrombin-induced human platelet activation and aggregation2019In: Cellular Signalling, ISSN 0898-6568, E-ISSN 1873-3913, Vol. 59, p. 96-109Article in journal (Refereed)
    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.

  • 10.
    Grenegård, Magnus
    et al.
    Örebro University, School of Medical Sciences.
    Koufaki, Maria
    Institute of Chemical Biology, National Hellenic Research Foundation, Athens, Greece.
    Zervou, Maria
    Institute of Chemical Biology, National Hellenic Research Foundation, Athens, Greece.
    Fotopoulou, Theano
    Institute of Chemical Biology, National Hellenic Research Foundation, Athens, Greece.
    Lindström, Eva
    Department of Biomedical and Clinical Sciences, Linköping University, Linköping, Sweden.
    Nilsson, Kristofer F.
    Örebro University, School of Medical Sciences. Örebro University Hospital.
    Lindkvist, Madelene
    Örebro University, School of Medical Sciences.
    Fransén, Karin
    Örebro University, School of Medical Sciences.
    The cardioprotective, anti-inflammatory and antithrombotic piperazinyl-purine analogue MK177 is a bifunctional drug with promising therapeutic potential2023In: British Journal of Pharmacology, ISSN 0007-1188, E-ISSN 1476-5381, Vol. 180, no Suppl. 1, p. 158-159, article id P0855Article in journal (Other academic)
    Abstract [en]

    Introduction: Nitrate ester bearing 6-piperazinyl-purine analogues (denoted MK drugs) are cardioprotective in infarction animal models and act as inhibitors of Janus kinase (JAK) and Rho-associated kinase (ROCK) [1-3]. Despite the presence of nitrate ester moiety, the MK drugs do not release nitric oxide (NO).

    Methods: We utilized organic chemistry platforms to design a dinitrate ester derivative denoted MK177, cell-free and cellular assays to elucidate antithrom-botic and anti-ischemic mechanisms. Furthermore, we also used tissue models to analyze vasodilation, and animal models to evaluate drug activities in vivo.

    Results: In anesthetized pigs, intravenous infusion of MK177 produced“nitroglycerin-like”effects on vital parameters. Analysis of exhaled air confirmed release of NO. MK177 caused concentration-dependent relaxation of iliac arteries (87±6.8 % relaxation of precontracted arteries, mean value ±SD, n=5) and this effect was mediated by activation of the NO/cyclic GMP signaling pathway. It is noteworthy that other mononitrate or non-nitrate MKs did not cause NO-induced vasodilation. In cellular model systems, MK177 evoked antithrombotic effects by targeting ROCK in a NO-independent manner. Specifically, MK177 inhibited platelet aggregation induced by collagen (72±12.6 % inhibition of aggregation, mean value±SD, n=7). Western blot analyses confirmed that MK177 reduced ROCK-dependent phosphorylation of myosin phosphatase sub-unit (MYPT-1) in platelets. Finally, kinase screening assay revealed that MK177 concentration-dependently inhibited ROCK and JAK (Kd values around 5μM).

    Conclusion: We have developed a bifunctional drug molecule, MK177, that acts by NO-dependent and NO-independent mechanisms. MK 177 induced car-diovascular NO effects in vivo and relaxed vessels in vitro. MK177 also prevented blood platelet activation via NO-independent ROCK inhibition. The bifunctional nature of MK177 can be of significance in future management of thrombotic and ischemic disease. Collectively, the novel cardio-protective and bifunctional drug MK177 has promising therapeutic potential.

    References:

    1. Koufaki M, Fotopoulou T, Iliodromitis EK, Bibli SI, Zoga A, Kremastinos DT, Andreadou I. Discovery of 6-[4-(6-nitroxyhexanoyl)(piperazin-1-yl)]-9H-purine, as pharmacological post-conditioning agent. Bioorg Med Chem. 2012;20(19):5948-5956. https://doi.org/10.1016/j.bmc.2012.07.037

    2. Kardeby C, Paramel GV, Pournara D, Fotopoulou T, Sirsjö A, Koufaki M, Fransén K, Grenegård M. A novel purine analogue bearing nitrate ester prevents platelet activation by ROCK activity inhibition. Eur J Pharmacol. 2019;15(857):172428-172434. https://doi.org/10.1016/j.ejphar.2019.172428

    3. Paramel GV, Lindkvist M, Idosa BA, Sebina LS, Kardeby C, Fotopoulou T, Pournara D, Kritsi E, Ifanti E, Zervou M, Koufaki M, Grenegård M, Fransén K. Novel purine analogues regulate IL-1βrelease via inhibition of JAK activity in human aortic smooth muscle cells. Eur J Pharmacol. 2022;15(929):175128-175135. https://doi.org/10.1016/j.ejphar.2022.175128

  • 11.
    Holm, Ann-Charlotte B. Svensson
    et al.
    Department of Clinical and Experimental Medicine, Faculty of Health Sciences, Linköping University, Linköping, Sweden; Department of Medical and Health Sciences, Faculty of Health Sciences, Linköping University, Linköping, Sweden.
    Grenegård, Magnus
    Örebro University, School of Medicine, Örebro University, Sweden. Department of Medical and Health Sciences, Faculty of Health Sciences, Linköping University, Linköping, Sweden; Department of Clinical Pathology and Clinical Genetics, County Council of Östergötland, Linköping, Sweden.
    Ollinger, Karin
    Department of Clinical and Experimental Medicine, Faculty of Health Sciences, Linköping University, Linköping, Sweden; Department of Clinical Pathology and Clinical Genetics, County Council of Östergötland, Linköping, Sweden.
    Lindström, Eva G.
    Department of Medical and Health Sciences, Faculty of Health Sciences, Linköping University, Linköping, Sweden.
    Inhibition of 12-lipoxygenase reduces platelet activation and prevents their mitogenic function2014In: Platelets, ISSN 0953-7104, E-ISSN 1369-1635, Vol. 25, no 2, p. 111-117Article in journal (Refereed)
    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-a-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.

  • 12.
    Junker, Johan P.E.
    et al.
    Division of Plastic Surgery, Department of Surgery, Brigham and Women’s Hospital, Harvard Medical School, Boston, USA; Division of Surgery, Department of Clinical and Experimental Medicine, Faculty of Health Sciences, Linköping University, Linköping, Sweden.
    Lönnqvist, Susanna
    Division of Surgery, Department of Clinical and Experimental Medicine, Faculty of Health Sciences, Linköping University, Linköping, Sweden; Department of Plastic Surgery, County of Östergötland, Linköping, Sweden.
    Rakar, Jonathan
    Division of Surgery, Department of Clinical and Experimental Medicine, Faculty of Health Sciences, Linköping University, Linköping, Sweden; Department of Plastic Surgery, County of Östergötland, Linköping, Sweden.
    Karlsson, Lisa K.
    Division of Surgery, Department of Clinical and Experimental Medicine, Faculty of Health Sciences, Linköping University, Linköping, Sweden; Department of Plastic Surgery, County of Östergötland, Linköping, Sweden.
    Grenegård, Magnus
    Department of Medical and Health Sciences, University Hospital of Linköping, Linköping, Sweden.
    Kratz, Gunnar
    Division of Surgery, Department of Clinical and Experimental Medicine, Faculty of Health Sciences, Linköping University, Linköping, Sweden; Department of Plastic Surgery, County of Östergötland, Linköping, Sweden.
    Differentiation of human dermal fibroblasts towards endothelial cells2013In: Differentiation, ISSN 0301-4681, E-ISSN 1432-0436, Vol. 85, no 3, p. 67-77Article in journal (Refereed)
    Abstract [en]

    The ultimate goal of vascular tissue engineering is the production of functional grafts for clinical use. Difficulties acquiring autologous endothelial cells have motivated the search for alternative cell sources. Differentiation of dermal fibroblasts towards several mesenchymal lineages as well as endothelial cells has been proposed. The aim of the present study was to investigate the endothelial differentiation capacity of human dermal fibroblasts on a gene expression, protein expression and functional physiological level. Endothelial differentiation of fibroblasts was induced by culturing cells in 30% human serum, but not in fetal calf serum. Expression of proteins and genes relevant for endothelial function and differentiation was increased after induction. Furthermore, fibroblasts exposed to 30% human serum displayed increased uptake of low-density lipoprotein and formation of capillary-like networks. The results of this study may have an impact on cell sourcing for vascular tissue engineering, and the development of methods for vascularization of autologous tissue engineered constructs.

  • 13.
    Kardeby, Caroline
    et al.
    Örebro University, School of Medical Sciences.
    Fälker, Knut
    Örebro University, School of Medical Sciences.
    Haining, Elizabeth J.
    Institute of Cardiovascular Sciences, College of Medical and Dental Sciences, University of Birmingham, Birmingham, United Kingdom.
    Criel, Maarten
    Center for Molecular and Vascular Biology, Department of Cardiovascular Sciences, University of Leuven, Leuven, Belgium.
    Lindkvist, Madelene
    Örebro University, School of Medical Sciences.
    Barroso, Ruben
    Institute of Cardiovascular Sciences, College of Medical and Dental Sciences, University of Birmingham, Birmingham, United Kingdom; Centre of Membrane Proteins and Receptors, Universities of Birmingham and Nottingham, The Midlands, United Kingdom.
    Påhlsson, Peter
    Division of Cell Biology, Department of Clinical and Experimental Medicine, Linköping University, Linköping, Sweden.
    Ljungberg, Liza
    Örebro University, School of Medical Sciences.
    Tengdelius, Mattias
    Division of Organic Chemistry, Linköping University, Linköping, Sweden.
    Rainger, G. Ed.
    Institute of Cardiovascular Sciences, College of Medical and Dental Sciences, University of Birmingham, Birmingham, United Kingdom.
    Watson, Stephanie
    Institute of Cardiovascular Sciences, College of Medical and Dental Sciences, University of Birmingham, Birmingham, United Kingdom.
    Eble, Johannes A.
    Institute of Physiological Chemistry and Pathobiochemistry, University of Münster, Münster, Germany.
    Hoylaerts, Marc F.
    Center for Molecular and Vascular Biology, Department of Cardiovascular Sciences, University of Leuven, Leuven, Belgium.
    Emsley, Jonas
    Centre of Membrane Proteins and Receptors, Universities of Birmingham and Nottingham, The Midlands, United Kingdom; Division of Biomolecular Science and Medicinal Chemistry, Centre for Biomolecular Sciences, School of Pharmacy, University of Nottingham, Nottingham, United Kingdom.
    Konradsson, Peter
    Division of Organic Chemistry, Linköping University, Linköping, Sweden.
    Watson, Steve P.
    Institute of Cardiovascular Sciences, College of Medical and Dental Sciences, University of Birmingham, Birmingham, United Kingdom; Centre of Membrane Proteins and Receptors, Universities of Birmingham and Nottingham, The Midlands, United Kingdom.
    Sun, Yi
    Institute of Cardiovascular Sciences, College of Medical and Dental Sciences, University of Birmingham, Birmingham, United Kingdom; Centre of Membrane Proteins and Receptors, Universities of Birmingham and Nottingham, The Midlands, United Kingdom.
    Grenegård, Magnus
    Örebro University, School of Medical Sciences.
    Synthetic glycopolymers and natural fucoidans cause human platelet aggregation via PEAR1 and GPIbα2019In: Blood Advances, ISSN 2473-9529 , E-ISSN 2473-9537, Vol. 3, no 3, p. 275-287Article in journal (Refereed)
    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.

  • 14.
    Kardeby, Caroline
    et al.
    Örebro University, School of Medical Sciences. Cardiovascular Research Centre (CVRC).
    Paramel Varghese, Geena
    Örebro University, School of Medical Sciences. Cardiovascular Research Centre (CVRC).
    Pournara, Dimitra
    National Hellenic Research Foundation, Institute of Biology, Medicinal Chemistry and Biotechnology, Athens, Greece.
    Fotopoulou, Theano
    National Hellenic Research Foundation, Institute of Biology, Medicinal Chemistry and Biotechnology, Athens, Greece.
    Sirsjö, Allan
    Örebro University, School of Medical Sciences. Cardiovascular Research Centre (CVRC).
    Koufaki, Maria
    National Hellenic Research Foundation, Institute of Biology, Medicinal Chemistry and Biotechnology, Athens, Greece.
    Fransén, Karin
    Örebro University, School of Medical Sciences. Cardiovascular Research Centre (CVRC).
    Grenegård, Magnus
    Örebro University, School of Medical Sciences. Cardiovascular Research Centre (CVRC).
    A novel purine analogue bearing nitrate ester prevents platelet activation by ROCK activity inhibitionManuscript (preprint) (Other academic)
  • 15.
    Kardeby, Caroline
    et al.
    Örebro University, School of Medical Sciences.
    Paramel Varghese, Geena
    Örebro University, School of Medical Sciences.
    Pournara, Dimitra
    National Hellenic Research Foundation, Institute of Biology, Medicinal Chemistry and Biotechnology, Athens, Greece.
    Fotopoulou, Theano
    National Hellenic Research Foundation, Institute of Biology, Medicinal Chemistry and Biotechnology, Athens, Greece.
    Sirsjö, Allan
    Örebro University, School of Medical Sciences.
    Koufaki, Maria
    National Hellenic Research Foundation, Institute of Biology, Medicinal Chemistry and Biotechnology, Athens, Greece.
    Fransén, Karin
    Örebro University, School of Medical Sciences.
    Grenegård, Magnus
    Örebro University, School of Medical Sciences.
    A novel purine analogue bearing nitrate ester prevents platelet activation by ROCK activity inhibition2019In: European Journal of Pharmacology, ISSN 0014-2999, E-ISSN 1879-0712, Vol. 857, article id 172428Article in journal (Refereed)
    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.

  • 16.
    Kardeby, Caroline
    et al.
    Örebro University, School of Medical Sciences. Cardiovascular Research Centre (CVRC).
    Sirsjö, Allan
    Örebro University, School of Medical Sciences. Cardiovascular Research Centre (CVRC).
    Ljungberg, Liza
    Örebro University, School of Medical Sciences. Cardiovascular Research Centre (CVRC).
    Grenegård, Magnus
    Örebro University, School of Medical Sciences. Cardiovascular Research Centre (CVRC).
    Sulfated glycopolymers and polysaccharides regulate inflammation-related proteins in human vascular endothelial cellsManuscript (preprint) (Other academic)
  • 17.
    Lindkvist, Madelene
    et al.
    Örebro University, School of Medical Sciences.
    Fernberg, Ulrika
    Örebro University, School of Medical Sciences.
    Ljungberg, Liza
    Örebro University, School of Medical Sciences.
    Fälker, Knut
    Örebro University, School of Medical Sciences.
    Fernström, Maria
    Örebro University, School of Health Sciences.
    Hurtig-Wennlöf, Anita
    Örebro University, School of Health Sciences.
    Grenegård, Magnus
    Örebro University, School of Medical Sciences.
    Individual variations in platelet reactivity towards ADP, epinephrine, collagen and nitric oxide, and the association to arterial function in young, healthy adults2019In: Thrombosis Research, ISSN 0049-3848, E-ISSN 1879-2472, Vol. 174, p. 5-12Article in journal (Refereed)
    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.

  • 18.
    Lindkvist, Madelene
    et al.
    Örebro University, School of Medical Sciences.
    Ljungberg, Liza U
    Örebro University, School of Medical Sciences.
    Fälker, Knut
    Örebro University, School of Medical Sciences.
    Ramström, Sofia
    Örebro University, School of Medical Sciences.
    Kardeby, Caroline
    Örebro University, School of Medical Sciences.
    Sirsjö, Allan
    Örebro University, School of Medical Sciences.
    Grenegård, Magnus
    Örebro University, School of Medical Sciences.
    IL-6 trans-signalling inhibits micro- and macro-aggregation induced by epinephrine in human plateletsManuscript (preprint) (Other academic)
  • 19.
    Lindkvist, Madelene
    et al.
    Örebro University, School of Medical Sciences.
    Zegeye, Mulugeta M
    Örebro University, School of Medical Sciences.
    Grenegård, Magnus
    Örebro University, School of Medical Sciences.
    Ljungberg, Liza
    Örebro University, School of Medical Sciences.
    Pleiotropic, Unique and Shared Responses Elicited by IL-6 Family Cytokines in Human Vascular Endothelial Cells2022In: International Journal of Molecular Sciences, ISSN 1661-6596, E-ISSN 1422-0067, Vol. 23, no 3, article id 1448Article in journal (Refereed)
    Abstract [en]

    Vascular endothelial cells express glycoprotein 130 (gp130), which is utilized as a signaling receptor by cytokines in the interleukin-6 (IL-6) family. Several IL-6 family cytokines can be found in the circulatory system during physiological or pathological conditions, and may influence endothelial function and response. This study evaluated and compared the cellular and molecular responses induced by IL-6 family cytokines in human endothelial cells. A proteomic analysis showed that IL-6 family cytokines induce the release of a range of proteins from endothelial cells, such as C-C motif chemokine ligand 23, hepatocyte growth factor, and IL-6. Pathway analysis indicated that gp130-signaling in endothelial cells regulates several functions related to angiogenesis and immune cell recruitment. The present investigation also disclosed differences and similarities between different IL-6 family cytokines in their ability to induce protein release and regulate gene expression and intracellular signaling, in regards to which oncostatin M showed the most pronounced effect. Further, this study showed that soluble gp130 preferentially blocks trans-signaling-induced responses, but does not affect responses induced by classic signaling. In conclusion, IL-6 family cytokines induce both specific and overlapping molecular responses in endothelial cells, and regulate genes and proteins involved in angiogenesis and immune cell recruitment.

  • 20.
    Lindkvist, Madelene
    et al.
    Örebro University, School of Medical Sciences.
    Zegeye, Mulugeta M
    Örebro University, School of Medical Sciences.
    Sirsjö, Allan
    Örebro University, School of Medical Sciences.
    Grenegård, Magnus
    Örebro University, School of Medical Sciences.
    Ljungberg, Liza U
    Örebro University, School of Medical Sciences.
    Comparative evaluation of gp130 signalling cytokines in human endothelial cells: evidence for both specific and overlapping molecular responsesManuscript (preprint) (Other academic)
  • 21.
    Lunde, Ngoc Nguyen
    et al.
    Section for Pharmacology and Pharmaceutical Biosciences, Department of Pharmacy, University of Oslo, Oslo, Norway.
    Gregersen, Ida
    Research Institute of Internal Medicine, Oslo University Hospital Rikshospitalet, Oslo, Norway; Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway.
    Ueland, Thor
    Research Institute of Internal Medicine, Oslo University Hospital Rikshospitalet, Oslo, Norway; Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway; K. G. Jebsen Thrombosis Research and Expertise Center, University of Tromsø, Tromsø, Norway.
    Shetelig, Christian
    Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway; Center for Clinical Heart Research, Department of Cardiology, Oslo University Hospital Ullevål, Oslo, Norway; Department of Cardiology, Oslo University Hospital Ullevål, Oslo, Norway.
    Holm, Sverre
    Research Institute of Internal Medicine, Oslo University Hospital Rikshospitalet, Oslo, Norway.
    Kong, Xiang Yi
    Research Institute of Internal Medicine, Oslo University Hospital Rikshospitalet, Oslo, Norway; Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway.
    Michelsen, Annika E.
    Research Institute of Internal Medicine, Oslo University Hospital Rikshospitalet, Oslo, Norway; Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway.
    Otterdal, Kari
    Research Institute of Internal Medicine, Oslo University Hospital Rikshospitalet, Oslo, Norway.
    Yndestad, Arne
    Research Institute of Internal Medicine, Oslo University Hospital Rikshospitalet, Oslo, Norway; Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway.
    Broch, Kaspar
    Department of Cardiology, Oslo University Hospital Rikshospitalet, Oslo, Norway; KG Jebsen Center for Cardiac Research, University of Oslo, Oslo, Norway and Center for Heart Failure Research, Oslo University Hospital, Oslo, Norway.
    Gullestad, Lars
    Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway; Department of Cardiology, Oslo University Hospital Rikshospitalet, Oslo, Norway; KG Jebsen Center for Cardiac Research, University of Oslo, Oslo, Norway and Center for Heart Failure Research, Oslo University Hospital, Oslo, Norway.
    Nyman, Tuula A.
    Proteomics Core Facility, Department of Immunology, Institute of Clinical Medicine, University of Oslo and Rikshospitalet Oslo, Oslo, Norway.
    Bendz, Bjorn
    Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway; Department of Cardiology, Oslo University Hospital Rikshospitalet, Oslo, Norway.
    Eritsland, Jan
    Oslo Univ Hosp Ulleval, Dept Cardiol, Oslo, Norway..
    Hoffmann, Pavel
    Section of Interventional Cardiology, Oslo University Hospital Ullevål, Oslo, Norway.
    Skagen, Karolina
    Department of Neurology, Oslo University Hospital Rikshospitalet, Oslo, Norway.
    Goncalves, Isabel
    Experimental Cardiovascular Research Unit, Dept. of Clinical Sciences, Malmö Lund University, Malmö, Sweden.
    Nilsson, Jan
    Experimental Cardiovascular Research Unit, Dept. of Clinical Sciences, Malmö Lund University, Malmö, Sweden.
    Grenegård, Magnus
    Örebro University, School of Medical Sciences.
    Poreba, Marcin
    Department of Bioorganic Chemistry, Faculty of Chemistry, Wroclaw University of Technology, Wroclaw, Poland.
    Drag, Marcin
    Department of Bioorganic Chemistry, Faculty of Chemistry, Wroclaw University of Technology, Wroclaw, Poland.
    Seljeflot, Ingebjorg
    Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway; Center for Clinical Heart Research, Department of Cardiology, Oslo University Hospital Ullevål, Oslo, Norway; Department of Cardiology, Oslo University Hospital Ullevål, Oslo, Norway.
    Sporsheim, Bjornar
    Centre of Molecular Inflammation Research, Department of Clinical and Molecular Medicine, Norwegian University of Science and Technology, Trondheim, Norway.
    Espevik, Terje
    Centre of Molecular Inflammation Research, Department of Clinical and Molecular Medicine, Norwegian University of Science and Technology, Trondheim, Norway.
    Skjelland, Mona
    Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway; Department of Neurology, Oslo University Hospital Rikshospitalet, Oslo, Norway.
    Johansen, Harald Thidemann
    Section for Pharmacology and Pharmaceutical Biosciences, Department of Pharmacy, University of Oslo, Oslo, Norway.
    Solberg, Rigmor
    Section for Pharmacology and Pharmaceutical Biosciences, Department of Pharmacy, University of Oslo, Oslo, Norway.
    Aukrust, Pål
    Research Institute of Internal Medicine, Oslo University Hospital Rikshospitalet, Oslo, Norway; Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway; K. G. Jebsen Thrombosis Research and Expertise Center, University of Tromsø, Tromsø, Norway; Section of Clinical Immunology and Infectious Diseases, Oslo University Hospital Rikshospitalet, Oslo, Norway.
    Björkbacka, Harry
    Experimental Cardiovascular Research Unit, Dept. of Clinical Sciences, Malmö Lund University, Malmö, Sweden.
    Andersen, Geir Oystein
    Center for Clinical Heart Research, Department of Cardiology, Oslo University Hospital Ullevål, Oslo, Norway; Department of Cardiology, Oslo University Hospital Ullevål, Oslo, Norway.
    Halvorsen, Bente
    Research Institute of Internal Medicine, Oslo University Hospital Rikshospitalet, Oslo, Norway; Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway.
    Legumain is upregulated in acute cardiovascular events and associated with improved outcome - potentially related to anti-inflammatory effects on macrophages2020In: Atherosclerosis, ISSN 0021-9150, E-ISSN 1879-1484, Vol. 296, p. 74-82Article in journal (Refereed)
    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.

  • 22.
    Paramel Varghese, Geena
    et al.
    Örebro University, School of Medical Sciences.
    Lindkvist, Madelene
    Örebro University, School of Medical Sciences.
    Idosa, Berhane A.
    School of Medical Sciences, Örebro University, Örebro, Sweden.
    Sebina, Laila Sharon
    School of Medical Sciences, Örebro University, Örebro, Sweden.
    Kardeby, Caroline
    School of Medical Sciences, Örebro University, Örebro, Sweden; Institute of Cardiovascular Sciences, College of Medical and Dental Sciences, University of Birmingham, Birmingham, West Midlands, United Kingdom.
    Fotopoulou, Theano
    Institute of Chemical Biology, National Hellenic Research Foundation, Athens, Greece.
    Pournara, Dimitra
    Institute of Chemical Biology, National Hellenic Resear.
    Kritsi, Eftichia
    Institute of Chemical Biology, National Hellenic Resear.
    Ifanti, Eleni
    Institute of Chemical Biology, National Hellenic Resear.
    Zervou, Maria
    Institute of Chemical Biology, National Hellenic Resear.
    Koufaki, Maria
    Institute of Chemical Biology, National Hellenic Resear.
    Grenegård, Magnus
    Örebro University, School of Medical Sciences.
    Fransén, Karin
    Örebro University, School of Medical Sciences.
    Novel purine analogues regulate IL-1β release via inhibition of JAK activity in human aortic smooth muscle cells2022In: European Journal of Pharmacology, ISSN 0014-2999, E-ISSN 1879-0712, Vol. 929, article id 175128Article in journal (Refereed)
    Abstract [en]

    Purine analogues bearing a nitrate ester motif were previously discovered as cardioprotective and anti-inflammatory agents, but the anti-inflammatory mechanism remains to be established. We therefore investigated the anti-inflammatory effect of two purine analogues, MK118 bearing a nitrate ester moiety and the methyl-substituted analogue MK196 in Aortic Smooth Muscle Cells (AoSMCs), with emphasis on IL-1β release. The AoSMCs were stimulated with LPS with or without purine analogue, followed by ELISA, Olink proteomics, Western blot and real time PCR of NLRP3 inflammasome components. Both purine analogues inhibited the release of proteins involved in inflammation, such as TRAIL, CCL4, CSF1 and IL-1β in AoSMCs, as well as intracellular gene and protein expression of IL-1β and NLRP3 inflammasome components. MK196, but not MK118, also inhibited the LPS-induced release of IL-7, CXCL10, PD-L1, FLT3L and CCL20. We also showed that MK118 and possibly MK196 act via inhibition of JAKs. In silico studies showed that the purine moiety is a competent hinge binding motif and that the purine-piperazine scaffold is well accommodated in the lipophilic groove of JAK1-3. Both compounds establish interactions with catalytic amino acids in the active site of JAK1-3 and the terminal nitrate ester of MK118 was revealed as a promising pharmacophore. Our data suggest that MK118 and MK196 inhibit the release of proinflammatory proteins in AoSMCs, and targets JAK1-3 activation. Purine analogues also inhibit the expression of NLRP3 inflammasome genes and proteins and may in the future be evaluated for anti-inflammatory aspects on inflammatory diseases.

  • 23.
    Peng, Xiang
    et al.
    Department of Nephrology, Qingyuan City Hospital of Jinan University, Guangdong, China; Department of Medical and Health Sciences, Linköping University, Linköping, Sweden.
    Ramström, Sofia
    Department of Experimental and Clinical Medicine, Linköping University, Linköping, Sweden.
    Kurz, Tino
    Department of Medical and Health Sciences, Linköping University, Linköping, Sweden.
    Grenegård, Magnus
    Örebro University, School of Medicine, Örebro University, Sweden. Department of Medical and Health Sciences, Linköping University, Linköping, Sweden; .
    Segelmark, Mårten
    Department of Medical and Health Sciences, Linköping University, Linköping, Sweden.
    The neutrophil serine protease PR3 induces shape change of platelets via the Rho/Rho kinase and Ca2+ signaling pathways2014In: Thrombosis Research, ISSN 0049-3848, E-ISSN 1879-2472, Vol. 134, no 2, p. 418-425Article in journal (Refereed)
    Abstract [en]

    Introduction: Proteinase 3 (PR3) is released from neutrophil azurophilic granules and exerts complex effects on the inflammatory process. PR3 catalyzes the degradation of a number of macromolecules, but the consequences on blood cells are less well defined. In the present study, the effect of PR3 on human platelets was thoroughly investigated.

    Methods: The experiments were performed on washed platelets freshly isolated from blood donated by healthy human volunteers. Platelets shape change and aggregation was measured on a Chrono-Log aggregometer. The phosphorylated form of MYPT1 was visualized by immunostaining. Platelet activation was further evaluated by flow cytometry.

    Results: PR3 induced platelet shape change but not aggregation. Flow cytometry analysis showed that PR3 induced no P-selectin expression or binding of fibrinogen to the platelets, and it did not change the activation in response to PAR1- or PAR4-activating peptides or to thrombin. Furthermore, Fura-2 measurement and immuno-blotting analysis, respectively, revealed that PR3 stimulated small intracellular Ca2+ mobilization and Thr696-specific phosphorylation of the myosin phosphatase target subunit 1 (MYPT1). Separate treatment of platelets with the Rho/Rho kinase inhibitor Y-27632 and the intracellular Ca2+ chelator BAPTA/AM reduced the shape change induced by PR3 whereas concurrent treatment completely inhibited it.

    Conclusion: The data shows that the neutrophil protease PR3 is a direct modulator of human platelets and causes shape change through activation of the Rho/Rho kinase and Ca2+ signaling pathways. This finding highlights an additional mechanism in the complex interplay between neutrophils and platelets.

  • 24.
    Sodergren, Anna L.
    et al.
    Department of Clinical and Experimental Medicine, Faculty of Health Sciences, Linköping University, Linköping, Sweden.
    Holm, Ann-Charlotte B. Svensson
    Department of Clinical and Experimental Medicine, Faculty of Health Sciences, Linköping University, Linköping, Sweden.
    Ramström, Sofia
    Department of Clinical and Experimental Medicine, Faculty of Health Sciences, Linköping University, Linköping, Sweden.
    Lindström, Eva G.
    Department of Medical and Health Sciences, Faculty of Health Sciences, Linkoöping University, Linköping, Sweden.
    Grenegård, Magnus
    Örebro University, School of Medical Sciences. Department of Medical and Health Sciences, Faculty of Health Sciences, Linkoöping University, Linköping, Sweden; Department of Clinical Medicine, Örebro University Hospital, Örebro, Sweden.
    Öllinger, Karin
    Department of Clinical and Experimental Medicine, Faculty of Health Sciences, Linköping University, Linköping, Sweden.
    Thrombin-induced lysosomal exocytosis in human platelets is dependent on secondary activation by ADP and regulated by endothelial-derived substances2016In: Platelets, ISSN 0953-7104, E-ISSN 1369-1635, Vol. 27, no 1, p. 86-92Article in journal (Refereed)
    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.

  • 25.
    Tengdelius, Mattias
    et al.
    Division of Organic Chemistry, Department of Physics, Biology and Chemistry (IFM), Linköping University, Linköping , Sweden.
    Kardeby, Caroline
    Örebro University, School of Medical Sciences.
    Fälker, Knut
    Örebro University, School of Medical Sciences.
    Griffith, May
    Division of Cell Biology, Department of Clinical and Experimental Medicine (IKE), Linköping University, Linköping, Sweden.
    Påhlsson, Peter
    Division of Cell Biology, Department of Clinical and Experimental Medicine (IKE), Linköping University, Linköping, Sweden.
    Konradsson, Peter
    Division of Organic Chemistry, Department of Physics, Biology and Chemistry (IFM), Linköping University, Linköping , Sweden.
    Grenegård, Magnus
    Örebro University, School of Medical Sciences.
    Fucoidan-Mimetic Glycopolymers as Tools for Studying Molecular and Cellular Responses in Human Blood Platelets2017In: Macromolecular Bioscience, ISSN 1616-5187, E-ISSN 1616-5195, Vol. 17, no 2, article id UNSP 1600257Article in journal (Refereed)
    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.

  • 26.
    Tengdelius, Mattias
    et al.
    Division of Organic Chemistry, Department of Physics, Biology and Chemistry (IFM), Linköping University, Linköping, Sweden; Integrative Regenerative Medicine Center (IGEN), Linköping University, Linköping, Sweden.
    Lee, Chyan-Jang
    Division of Organic Chemistry, Department of Physics, Biology and Chemistry (IFM), Linköping University, Linköping, Sweden; Division of Cell Biology, Department of Clinical and Experimental Medicine (IKE), Linköping University, Linköping, Sweden; Integrative Regenerative Medicine Center (IGEN), Linköping University, Linköping, Sweden.
    Grenegård, Magnus
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden. Integrative Regenerative Medicine Center (IGEN), Linköping University, Linköping, Sweden.
    Griffith, May
    Division of Molecular Physics, Department of Physics, Biology and Chemistry (IFM), Linköping University, Linköping, Sweden; Division of Cell Biology, Department of Clinical and Experimental Medicine (IKE), Linköping University, Linköping, Sweden; Integrative Regenerative Medicine Center (IGEN), Linköping University, Linköping, Sweden.
    Påhlsson, Peter
    Division of Cell Biology, Department of Clinical and Experimental Medicine (IKE), Linköping University, Linköping, Sweden; Integrative Regenerative Medicine Center (IGEN), Linköping University, Linköping, Sweden.
    Konradsson, Peter
    Division of Organic Chemistry, Department of Physics, Biology and Chemistry (IFM), Linköping University, Linköping, Sweden.
    Synthesis and Biological Evaluation of Fucoidan-Mimetic Glycopolymers through Cyanoxyl-Mediated Free-Radical Polymerization2014In: Biomacromolecules, ISSN 1525-7797, E-ISSN 1526-4602, Vol. 15, no 7, p. 2359-2368Article in journal (Refereed)
    Abstract [en]

    The sulfated marine polysaccharide fucoidan has been reported to have health benefits ranging from antivirus and anticancer properties to modulation of high blood pressure. Hence, they could enhance the biological function of materials for biomedical applications. However, the incorporation of fucoidan into biomaterials has been difficult, possibly due to its complex structure and lack of suitable functional groups for covalent anchoring to biomaterials. We have developed an approach for a rapid synthesis of fucoidanmimetic glycopolymer chains through cyanoxyl-mediated freeradical polymerization, a method suitable for chain-end functionalizing and subsequent linkage to biomaterials. The resulting sulfated and nonsulfated methacrylamido α-L-fucoside glycopolymers’ fucoidan-mimetic properties were studied in HSV-1 infection and platelet activation assays. The sulfated glycopolymer showed similar properties to natural fucoidan in inducing platelet activation and inhibiting HSV-1 binding and entry to cells, thus indicating successful syntheses of fucoidan-mimetic glycopolymers.

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  • 27.
    Wenglén, Christina
    et al.
    ANAMAR, Lund, Sweden.
    Demirel, Isak
    Örebro University, School of Medical Sciences.
    Göthlin Eremo, Anna
    Örebro University, School of Medical Sciences. Department of Clinical Research Laboratory, Faculty of Medicine, and Health, Örebro University, Örebro, Sweden.
    Grenegård, Magnus
    Örebro University, School of Medical Sciences. Cardiovascular Research Centre, School of Medical Sciences, Örebro University, Örebro, Sweden.
    Paramel Varghese, Geena
    Örebro University, School of Medical Sciences. Cardiovascular Research Centre, School of Medical Sciences, Örebro University, Örebro, Sweden.
    Targeting serotonin receptor 2B inhibits TGFβ induced differentiation of human vascular smooth muscle cells2023In: European Journal of Pharmacology, ISSN 0014-2999, E-ISSN 1879-0712, Vol. 944, article id 175570Article in journal (Refereed)
    Abstract [en]

    Vascular smooth muscles (VSMCs) are known to be the key drivers of intimal thickening which contribute to early progression of atherosclerosis. VSMCs are the major producers of extracellular matrix within the vessel wall and in response to atherogenic stimuli they could modify the type of matrix proteins produced. Serotonin receptor 2B (5-HT2B receptor/HTR2B) has been implicated in several chronic fibrotic and vascular diseases. Although studies have successfully demonstrated the efficacy of HTR2B blockade in attenuating fibrotic disease, the role of 5-HT2B receptor in TGFβ mediated VSMC differentiation remain largely unknown. In the present study, we investigated the potential of targeting the 5-HT2B receptor to prevent TGFβ induced VSMCs differentiation. Our results showed that 5-HT2B receptors are expressed in human atherosclerotic lesion and HTR2B expression positively correlated to the VSMCs markers. We show that AM1125, a selective 5-HT2B receptor inhibitor, significantly inhibits TGFβ1 induced production of collagen and CTGF. The investigation of underlying mechanisms indicated that 5-HT2B receptor antagonism blocks phospho-Smad2 mediated downstream signaling of TGFβ1 in vascular smooth muscle cells. Collectively, the HTR2B/TGF-β1/Phospho-Smad2 pathway plays a critical role in the regulation of VSMCs differentiation. Our findings might serve 5-HT2B receptor as a therapeutic target to limit TGF-β1 induced VSMC differentiation.

  • 28.
    Zegeye, Mulugeta M.
    et al.
    Örebro University, School of Medical Sciences.
    Lindkvist, Madelene
    Örebro University, School of Medical Sciences.
    Fälker, Knut
    Örebro University, School of Medical Sciences.
    Kumawat, Ashok K.
    Örebro University, School of Medical Sciences.
    Paramel Varghese, Geena
    Örebro University, School of Medical Sciences. Department of Biochemistry and Molecular Biology, Faculty of Medicine, Dalhousie University, Dalhousie Medicine New Brunswick, Saint John, Canada.
    Grenegård, Magnus
    Örebro University, School of Medical Sciences.
    Sirsjö, Allan
    Örebro University, School of Medical Sciences.
    Ljungberg, Liza U.
    Örebro University, School of Medical Sciences.
    Activation of the JAK/STAT3 and PI3K/AKT pathways are crucial for IL-6 trans-signaling-mediated pro-inflammatory response in human vascular endothelial cells2018In: Cell Communication and Signaling, E-ISSN 1478-811X, Vol. 16, no 1, article id 55Article in journal (Refereed)
    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.

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    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
  • 29.
    Zegeye, Mulugeta M
    et al.
    Örebro University, School of Medical Sciences.
    Matic, Ljubica
    Department of Molecular Medicine and Surgery, Karolinska Institute, Stockholm, Sweden.
    Lengquist, Mariette
    Department of Molecular Medicine and Surgery, Karolinska Institute, Stockholm, Sweden.
    Hayderi, Assim
    Örebro University, School of Medical Sciences.
    Grenegård, Magnus
    Örebro University, School of Medical Sciences.
    Hedin, Ulf
    Department of Molecular Medicine and Surgery, Karolinska Institute, Stockholm, Sweden.
    Sirsjö, Allan
    Örebro University, School of Medical Sciences.
    Ljungberg, Liza U.
    Örebro University, School of Medical Sciences.
    Kumawat, Ashok Kumar
    Örebro University, School of Medical Sciences.
    Interleukin-6 trans-signaling induced laminin switch contributes to reduced trans-endothelial migration of granulocytic cells2023In: Atherosclerosis, ISSN 0021-9150, E-ISSN 1879-1484, Vol. 371, p. 41-53Article in journal (Refereed)
    Abstract [en]

    BACKGROUND AND AIMS: Laminins are essential components of the endothelial basement membrane, which predominantly contains LN421 and LN521 isoforms. Regulation of laminin expression under pathophysiological conditions is largely unknown. In this study, we aimed to investigate the role of IL-6 in regulating endothelial laminin profile and characterize the impact of altered laminin composition on the phenotype, inflammatory response, and function of endothelial cells (ECs).

    METHODS: HUVECs and HAECs were used for in vitro experiments. Trans-well migration experiments were performed using leukocytes isolated from peripheral blood of healthy donors. The BiKE cohort was used to assess expression of laminins in atherosclerotic plaques and healthy vessels. Gene and protein expression was analyzed using Microarray/qPCR and proximity extension assay, ELISA, immunostaining or immunoblotting techniques, respectively.

    RESULTS: Stimulation of ECs with IL-6+sIL-6R, but not IL-6 alone, reduces expression of laminin α4 (LAMA4) and increases laminin α5 (LAMA5) expression at the mRNA and protein levels. In addition, IL-6+sIL-6R stimulation of ECs differentially regulates the release of several proteins including CXCL8 and CXCL10, which collectively were predicted to inhibit granulocyte transmigration. Experimentally, we demonstrated that granulocyte migration is inhibited across ECs pre-treated with IL-6+sIL-6R. In addition, granulocyte migration across ECs cultured on LN521 was significantly lower compared to LN421. In human atherosclerotic plaques, expression of endothelial LAMA4 and LAMA5 is significantly lower compared to control vessels. Moreover, LAMA5-to-LAMA4 expression ratio was negatively correlated with granulocytic cell markers (CD177 and myeloperoxidase (MPO)) and positively correlated with T-lymphocyte marker CD3.

    CONCLUSIONS: We showed that expression of endothelial laminin alpha chains is regulated by IL-6 trans-signaling and contributes to inhibition of trans-endothelial migration of granulocytic cells. Further, expression of laminin alpha chains is altered in human atherosclerotic plaques and is related to intra-plaque abundance of leukocyte subpopulations.

  • 30.
    Venizelos, Nikolaos (Editor, Creator)
    Örebro University, School of Medical Sciences.
    Sirsjö, Allan (Editor, Creator)
    Örebro University, School of Medical Sciences.
    Ljungqvist, Olle (Editor, Creator)
    Örebro University, School of Medical Sciences.
    Nilsson, Ulrica (Editor, Creator)
    Örebro University, School of Health Sciences.
    Grenegård, Magnus (Editor, Creator)
    Örebro University, School of Medical Sciences.
    Eriksson, Charli (Editor, Creator)
    Örebro University, School of Health Sciences.
    Ericsson, Christer (Editor, Creator)
    Örebro University, School of Health Sciences.
    Örebro University’s Nobel Day Festivities: Book of abstracts 20132013Book (Other academic)
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  • 31.
    Venizelos, Nikolaos (Editor, Creator)
    Örebro University, School of Medical Sciences.
    Sirsjö, Allan (Editor, Creator)
    Örebro University, School of Medical Sciences.
    Ljungqvist, Olle (Editor, Creator)
    Örebro University, School of Medical Sciences.
    Kihlgren, Annica (Editor, Creator)
    Örebro University, School of Health Sciences.
    Grenegård, Magnus (Editor, Creator)
    Örebro University, School of Medical Sciences.
    Möller, Claes (Editor, Creator)
    Örebro University, School of Health Sciences.
    Danermark, Berth (Editor, Creator)
    Örebro University, School of Health Sciences.
    Eriksson, Charli (Editor, Creator)
    Örebro University, School of Health Sciences.
    Ericsson, Christer (Editor, Creator)
    Örebro University, School of Health Sciences.
    Kadi, Fawzi (Editor, Creator)
    Örebro University, School of Health Sciences.
    Örebro University’s Nobel Day Festivities: Book of abstracts 20142014Book (Other academic)
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  • 32.
    Venizelos, Nikolaos (Editor, Creator)
    Örebro University, School of Medical Sciences.
    Sirsjö, Allan (Editor, Creator)
    Örebro University, School of Medical Sciences.
    Grenegård, Magnus (Editor, Creator)
    Örebro University, School of Medical Sciences.
    Karlsson, Mats (Editor, Creator)
    Örebro University, School of Medical Sciences.
    Örebro University’s Nobel Day Festivities: Book of abstracts 20152015Book (Other academic)
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  • 33.
    Venizelos, Nikolaos (Editor, Creator)
    Örebro University, School of Science and Technology. Örebro University, School of Medical Sciences.
    Sirsjö, Allan (Editor, Creator)
    Örebro University, School of Medical Sciences.
    Grenegård, Magnus (Editor, Creator)
    Örebro University, School of Medical Sciences.
    Karlsson, Mats (Editor, Creator)
    Örebro University, School of Medical Sciences.
    Andersson, Sören (Editor, Creator)
    Örebro University, School of Medical Sciences.
    Hjelmqvist, Hans (Editor, Creator)
    Örebro University, School of Medical Sciences.
    Ericsson, Elisabeth (Editor, Creator)
    Örebro University, School of Health Sciences.
    Kihlgren, Annica (Editor, Creator)
    Örebro University, School of Health Sciences.
    Söderquist, Bo (Editor, Creator)
    Örebro University, School of Medical Sciences.
    Örebro University’s Nobel Day Festivities: Book of abstracts, 20162016Book (Other academic)
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