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  • 1.
    Engstrom Klarstrom, K
    et al.
    University of Örebro.
    Skoglund, C
    Linköping University, Department of Physics, Chemistry and Biology. Linköping University, The Institute of Technology.
    Kälvegren, Hanna
    Linköping University, Department of Medical and Health Sciences, Cardiology. Linköping University, Faculty of Health Sciences.
    Bengtsson, T
    University of Örebro.
    The role of platelets in inflammation at sites of infection; toll like receptor 2/1 mediated platelet adhesion on bacterial peptide-mimetic surfaces in CARDIOVASCULAR RESEARCH, vol 93, issue , pp S8-S82012In: CARDIOVASCULAR RESEARCH, Oxford University Press (OUP): Policy B , 2012, Vol. 93, p. S8-S8Conference paper (Refereed)
    Abstract [en]

    n/a

  • 2.
    Jönsson, Simon
    et al.
    Linköping University, Department of Medical and Health Sciences. Linköping University, Faculty of Health Sciences.
    Kälvegren, Hanna
    Linköping University, Department of Medical and Health Sciences. Linköping University, Faculty of Health Sciences.
    Lundberg, A
    Linköping University, Department of Medical and Health Sciences. Linköping University, Faculty of Health Sciences.
    Jonasson, Lena
    Linköping University, Department of Medical and Health Sciences, Cardiology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Heart and Medicine Centre, Department of Cardiology UHL.
    Neutrophils but not platelets are a major source of MMP-9 in coronary artery disease in EUROPEAN HEART JOURNAL, vol 31, issue , pp 486-4872010In: EUROPEAN HEART JOURNAL, Oxford University Press , 2010, Vol. 31, p. 486-487Conference paper (Refereed)
    Abstract [en]

    n/a

  • 3.
    Jönsson, Simon
    et al.
    Linköping University, Department of Medical and Health Sciences, Cardiology. Linköping University, Faculty of Health Sciences.
    Lundberg, Anna
    Linköping University, Department of Medical and Health Sciences, Cardiology. Linköping University, Faculty of Health Sciences.
    Kälvegren, Hanna
    Linköping University, Department of Medical and Health Sciences, Cardiology. Linköping University, Faculty of Health Sciences.
    Bergström, Ida
    Linköping University, Department of Medical and Health Sciences, Cardiology. Linköping University, Faculty of Health Sciences.
    Szymanowski, Aleksander
    Linköping University, Department of Medical and Health Sciences, Cardiology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Heart and Medicine Centre, Department of Cardiology UHL.
    Jonasson, Lena
    Linköping University, Department of Medical and Health Sciences, Cardiology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Heart and Medicine Centre, Department of Cardiology UHL.
    Increased Levels of Leukocyte-Derived MMP-9 in Patients with Stable Angina Pectoris2011In: PLOS ONE, ISSN 1932-6203, Vol. 6, no 4Article in journal (Refereed)
    Abstract [en]

    Objective: There is a growing interest for matrix metalloproteinases (MMPs) and their tissue inhibitors (TIMPs) in plasma as novel biomarkers in coronary artery disease (CAD). We aimed to identify the sources of MMP-8, MMP-9, TIMP-1 and TIMP-2 among peripheral blood cells and further explore whether gene expression or protein release was altered in patients with stable angina pectoris (SA). Methods: In total, plasma MMP-9 was measured in 44 SA patients and 47 healthy controls. From 10 patients and 10 controls, peripheral blood mononuclear cells (PBMC) and neutrophils were isolated and stimulated ex vivo. MMPs, TIMPs and myeloperoxidase were measured in plasma and supernatants by ELISA. The corresponding gene expression was measured by real-time PCR. Results: Neutrophils were the dominant source of MMP-8 and MMP-9. Upon moderate stimulation with IL-8, the neutrophil release of MMP-9 was higher in the SA patients compared with controls (p andlt; 0.05). In PBMC, the TIMP-1 and MMP-9 mRNA expression was higher in SA patients compared with controls, p andlt; 0.01 and 0.05, respectively. There were no differences in plasma levels between patients and controls except for TIMP-2, which was lower in patients, p andlt; 0.01. Conclusion: Measurements of MMPs and TIMPs in plasma may be of limited use. Despite similar plasma levels in SA patients and controls, the leukocyte-derived MMP-9 and TIMP-1 are significantly altered in patients. The findings indicate that the leukocytes are more prone to release and produce MMP-9 in symptomatic and angiographically verified CAD-a phenomenon that may have clinical implications in the course of disease.

  • 4.
    Klarstrom Engstrom, K.
    et al.
    University of Örebro, Sweden.
    Khalaf, H.
    University of Örebro, Sweden.
    Kälvegren, Hanna
    Linköping University, Department of Medical and Health Sciences, Division of Cardiovascular Medicine. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Heart and Medicine Center, Department of Cardiology in Linköping.
    Bengtsson, T.
    University of Örebro, Sweden.
    The role of Porphyromonas gingivalis gingipains in platelet activation and innate immune modulation2015In: Molecular Oral Microbiology, ISSN 2041-1006, E-ISSN 2041-1014, Vol. 30, no 1, p. 62-73Article in journal (Refereed)
    Abstract [en]

    Platelets are considered to have important functions in inflammatory processes and as actors in the innate immunity. Several studies have shown associations between cardiovascular disease and periodontitis, where the oral anaerobic pathogen Porphyromonas gingivalis has a prominent role in modulating the immune response. Porphyromonas gingivalis has been found in atherosclerotic plaques, indicating spreading of the pathogen via the circulation, with an ability to interact with and activate platelets via e.g. Toll-like receptors (TLR) and protease-activated receptors. We aimed to evaluate how the cysteine proteases, gingipains, of P.gingivalis affect platelets in terms of activation and chemokine secretion, and to further investigate the mechanisms of platelet-bacteria interaction. This study shows that primary features of platelet activation, i.e. changes in intracellular free calcium and aggregation, are affected by P.gingivalis and that arg-gingipains are of great importance for the ability of the bacterium to activate platelets. The P.gingivalis induced a release of the chemokine RANTES, however, to a much lower extent compared with the TLR2/1-agonist Pam(3)CSK(4), which evoked a time-dependent release of the chemokine. Interestingly, the TLR2/1-evoked response was abolished by a following addition of viable P.gingivalis wild-types and gingipain mutants, showing that both Rgp and Kgp cleave the secreted chemokine. We also demonstrate that Pam(3)CSK(4)-stimulated platelets release migration inhibitory factor and plasminogen activator inhibitor-1, and that also these responses were antagonized by P.gingivalis. These results supports immune-modulatory activities of P.gingivalis and further clarify platelets as active players in innate immunity and in sensing bacterial infections, and as target cells in inflammatory reactions induced by P.gingivalis infection.

  • 5.
    Klarstrom Engstrom, Kristin
    et al.
    University of Örebro, Sweden.
    Skoglund, Caroline
    Linköping University, Department of Physics, Chemistry and Biology, Molecular Surface Physics and Nano Science. Linköping University, The Institute of Technology.
    Kälvegren, Hanna
    Linköping University, Department of Medical and Health Sciences, Division of Cardiovascular Medicine. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Heart and Medicine Center, Department of Cardiology in Linköping.
    Bengtsson, Torbjoern
    University of Örebro, Sweden.
    Toll like receptor 2/1 mediated platelet adhesion and activation on bacterial mimetic surfaces is dependent on src/Syk-signaling and purinergic receptor P2X1 and P2Y12 activation2014In: BIOINTERPHASES, ISSN 1934-8630, Vol. 9, no 4, p. 041003-Article in journal (Refereed)
    Abstract [en]

    Platelets are considered to have important functions in inflammatory processes as key players in innate immunity. Toll like receptors (TLRs), expressed on platelets, recognize pathogen associated molecular patterns and trigger immune responses. Pathogens are able to adhere to human tissues and form biofilms which cause a continuous activation of the immune system. The authors aimed to investigate how immobilized Pam(3)CSK(4) (a synthetic TLR2/1 agonist) and IgG, respectively, resembling a bacterial focus, affects adhesion and activation of platelets including release of two cytokines, regulated on activation normal T-cell expressed and secreted (RANTES) and macrophage migration inhibitory factor (MIF). The authors also aim to clarify the signaling downstream of TLR2/1 and Fc gamma RII (IgG receptor) and the role of adenine nucleotides in this process. Biolayers of Pam(3)CSK(4) and IgG, respectively, were confirmed by null-ellipsometry and contact angle measurements. Platelets were preincubated with signaling inhibitors for scr and Syk and antagonists for P2X1 or P2Y1 [adenosine triphosphate (ATP), adenosine diphosphate (ADP) receptors] prior to addition to the surfaces. The authors show that platelets adhere and spread on both Pam(3)CSK(4)- and IgG-coated surfaces and that this process is antagonized by scr and Syc inhibitors as well as P2X1 and P2Y antagonists. This suggests that Pam(3)CSK(4) activated platelets utilize the same pathway as Fc gamma RII. Moreover, the authors show that ATP-ligation of P2X1 is of importance for further platelet activation after TLR2/1-activation, and that P2Y12 is the prominent ADP-receptor involved in adhesion and spreading. RANTES and MIF were secreted over time from platelets adhering to the coated surfaces, but no MIF was released upon stimulation with soluble Pam(3)CSK(4). These results clarify the importance of TLR2/1 and Fc gamma RII in platelet adhesion and activation, and strengthen the role of platelets as an active player in sensing bacterial infections. (C) 2014 American Vacuum Society.

  • 6.
    Kälvegren, Hanna
    Linköping University, Department of Medicine and Health Sciences. Linköping University, Faculty of Health Sciences.
    The Role of Chlamydia pneumoniae-induced Platelet Activation in Cardiovascular Disease: In vitro and In vivo studies2007Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    The common risk factors for atherosclerosis, such as obesity, high cholesterol levels, sedentary lifestyle, diabetes and high alcohol intake, only explain approximately 50% of cardiovascular disease events. It is thereby important to identify new mechanisms that can stimulate the process of atherosclerosis. During the past decades, a wide range of investigations have demonstrated connections between infections by the respiratory bacterium Chlamydia pneumoniae and atherosclerosis. Earlier studies have focused on the interaction between C. pneumoniae and monocytes/macrophages, T-lymphocytes, smooth muscle cells and endothelial cells, which are present in the atherosclerotic plaque. However, another important player in atherosclerosis and which is also present in the plaques is the platelet. Activation of platelets can stimulate both initiation and progression of atherosclerosis and thrombosis, which is the ultimate endpoint of the disease. The aim of the present thesis was to investigate the capacity of C. pneumoniae to activate platelets and its role in atherosclerosis.

    The results show that C. pneumoniae at low concentrations binds to platelets and stimulates platelet aggregation, secretion, reactive oxygen species (ROS) production and oxidation of low-density lipoproteins (LDL), and that these effects are mediated by lipopolysaccharide (LPS). Activation of protein kinase C, nitric oxide synthase and 12-lipoxygenase (12-LOX) was required for platelet ROS production, whereas platelet aggregation was dependent on activation of GpIIb/IIIa. Pharmacological studies showed that the C. pneumoniae-induced platelet activation is prevented by inhibitors against 12-LOX, platelet activating factor (PAF) and the purinergic P2Y1 and P2Y12 receptors, but not against cyclooxygenase (COX). These findings were completely opposite to the effects of these inhibitors on collagen-stimulated platelets. We also present data from a clinical study indicating that percutaneous coronary intervention (PCI or balloon dilatation) leads to release of C. pneumoniae into the circulation, which causes platelet activation and LDL oxidation.

    In conclusion, these data support a role for C. pneumoniae-induced platelet activation in the process of atherosclerosis. Stimulation of platelets by C. pneumoniae leads to release of growth factors and cytokines, oxidation of LDL and platelet aggregation, which are processes that can stimulate both atherosclerosis and thrombosis. Development of novel drugs that prevent C. pneumoniae-platelet interaction by inhibiting 12-LOX and/or PAF, may be important in the future treatment of cardiovascular disease.

    List of papers
    1. Chlamydia pneumoniae binds to platelets and triggers P-selectin expression and aggregation: A causal role in cardiovascular disease?
    Open this publication in new window or tab >>Chlamydia pneumoniae binds to platelets and triggers P-selectin expression and aggregation: A causal role in cardiovascular disease?
    2003 (English)In: Arteriosclerosis, Thrombosis and Vascular Biology, ISSN 1079-5642, E-ISSN 1524-4636, Vol. 23, no 9, p. 1677-1683Article in journal (Refereed) Published
    Abstract [en]

    Objective - Evidence linking Chlamydia pneumoniae to atherosclerotic cardiovascular disease is expanding. Platelets are considered to play an essential role in cardiovascular diseases, however, so far platelets have not been associated with an infectious cause of atherosclerosis. This study aims to clarify the interaction between Cpneumoniae and platelets and possibly present a novel mechanism in the pathogenesis of atherosclerosis.

    Methods and Results - The effects of C pneumoniae on platelet aggregation and secretion were assessed with lumiaggregometry, and the ability of C pneumoniae to bind to platelets and stimulate expression of P-selectin was analyzed with flow cytometry. We found that Cpneumoniae, at a chlamydia:platelet ratio of 1:15, adheres to platelets and triggers P-selectin expression after 1 minute and causes an extensive aggregation and ATP secretion after 20 minutes of incubation. Inhibition of glycoprotein IIb/IIIa with Arg-Gly-Asp-Ser or abciximab markedly reduced C pneumoniae-induced platelet aggregation. Exposure of C pneumoniae to polymyxin B, but not elevated temperature, abolished the stimulatory effects on platelet activation, suggesting that chlamydial lipopolysaccharide has an active role. In contrast, other tested bacteria had no or only moderate effects on platelet functions.

    Conclusion - Our findings demonstrate a new concept of how C pneumoniae activates platelets and thereby may cause atherosclerosis and thrombotic vascular occlusion.

     

    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:liu:diva-14386 (URN)10.1161/01.ATV.0000084810.52464.D5 (DOI)
    Available from: 2007-04-20 Created: 2007-04-20 Last updated: 2017-12-13Bibliographically approved
    2. Chlamydia pneumoniae induces nitric oxide synthase and lipoxygenase-dependent production of reactive oxygen species in platelets — effects on oxidation of low-density lipoproteins.
    Open this publication in new window or tab >>Chlamydia pneumoniae induces nitric oxide synthase and lipoxygenase-dependent production of reactive oxygen species in platelets — effects on oxidation of low-density lipoproteins.
    Show others...
    2005 (English)In: Thrombosis and Haemostasis, ISSN 0340-6245, Vol. 94, no 2, p. 327-335Article in journal (Refereed) Published
    Abstract [en]

    There is increasing evidence that Chlamydia pneumoniae is linked to atherosclerosis and thrombosis. In this regard, we have recently shown that C. pneumoniae stimulates platelet aggregation and secretion, which may play an important role in the progress of atherosclerosis and in thrombotic vascular occlusion. The aims of the present study were to investigate the effects of C. pneumoniae on platelet-mediated formation of reactive oxygen species (ROS) and oxidation of low-density lipoprotein (LDL) in vitro. ROS production was registered as changes in 2´,7`-dichlorofluorescin- fluorescence in platelets with flow cytometry. LDL-oxidation was determined by measuring thiobarbituric acid reactive substances (TBARs). We found that C. pneumoniae stimulated platelet production of ROS.Polymyxin B treatment of C. pneumoniae, but not elevated temperature, abolished the stimulatory effects on platelet ROS- production, which suggests that chlamydial lipopolysaccharide has an important role. In hibition of nitric oxide synthase with nitro-L-arginine, lipoxygenase with 5,8,11-eicosatriynoic acid and protein kinase C with GF 109203X significantly lowered the production of radicals. In contrast, inhibition of NADPH-oxidase with di-phenyleneiodonium (DPI) did not affect the C. pneumoniae induced ROS-production. These findings suggest that the activities of nitric oxide synthase and lipoxygenase are the sources for ROS and that the generation is dependent of the activity of protein kinase C.The C. pneumoniae-induced ROS-production in platelets was associated with an extensive oxidation of LDL, which was significantly higher compared to the effect obtained by separate exposure of LDL to C. pneumoniae or platelets. In conclusion, C. pneumoniae interaction with platelets leading to aggregation, ROS-production and oxidative damage on LDL, may play a crucial role in the development of atherosclerotic cardiovascular disease.

    Keywords
    Atherosclerosis, bacteria-cell interaction, oxygen radical, LPS, thrombosis
    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:liu:diva-14387 (URN)10.1160/TH04-06-0360 (DOI)
    Available from: 2007-04-20 Created: 2007-04-20
    3. Correlation between rises in Chlamydia pneumoniae-specific antibodies, platelet activation and lipid peroxidation after percutaneous coronary intervention.
    Open this publication in new window or tab >>Correlation between rises in Chlamydia pneumoniae-specific antibodies, platelet activation and lipid peroxidation after percutaneous coronary intervention.
    Show others...
    2008 (English)In: European Journal of Clinical Microbiology and Infectious Diseases, ISSN 0934-9723, E-ISSN 1435-4373, Vol. 27, no 7, p. 503-511Article in journal (Refereed) Published
    Abstract [en]

    We recently showed that Chlamydia pneumoniae activates platelets in vitro, with an associated oxidation of low-density lipoproteins. The aim of this study was to investigate whether C. pneumoniae is released during percutaneous coronary intervention (PCI) and, thereby, causes platelet activation and lipid peroxidation. Seventy-three patients undergoing coronary angiography and following PCI or coronary artery bypass graft (CABG) and 57 controls were included in the study. C. pneumoniae antibodies, serotonin and lipid peroxidation were measured before and 24 h, 1 month and 6 months after angiography. The results show that serum C. pneumoniae IgA concentrations were significantly higher in patients than in the controls. Furthermore, in 38% of the C. pneumoniae IgG positive patients, the C. pneumoniae IgG concentration increased 1 month after PCI. The levels of C. pneumoniae IgG antibodies 1 month after PCI correlated with plasma-lipid peroxidation (r = 0.91, P < 0.0001) and platelet-derived serotonin (r = 0.62, P = 0.02). There was no elevation in the total serum IgG 1 month after PCI. In conclusion, the present results suggest that PCI treatment of coronary stenosis releases C. pneumoniae from the atherosclerotic lesions, which leads to platelet activation and lipid peroxidation.

    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:liu:diva-14388 (URN)10.1007/s10096-008-0465-y (DOI)
    Available from: 2007-04-20 Created: 2007-04-20 Last updated: 2017-12-13Bibliographically approved
    4. Platelet activation triggered by Chlamydia pneumoniae is antagonized by 12-lipoxygenase inhibitors but not cyclooxygenase inhibitors.
    Open this publication in new window or tab >>Platelet activation triggered by Chlamydia pneumoniae is antagonized by 12-lipoxygenase inhibitors but not cyclooxygenase inhibitors.
    2007 (English)In: European Journal of Pharmacology, ISSN 0014-2999, E-ISSN 1879-0712, Vol. 566, no 1-3, p. 20-27Article in journal (Refereed) Published
    Abstract [en]

    Chlamydia pneumoniae is a respiratory pathogen that has been linked to cardiovascular disease. We have recently shown that C. pneumoniae activates platelets, leading to oxidation of low-density lipoproteins. The aim of the present study was to evaluate the inhibitory effects of different pharmacological agents on platelet aggregation and secretion induced by C. pneumoniae.

    Platelet interaction with C. pneumoniae was studied by analyzing platelet aggregation and ATP-secretion with Lumi-aggregometry.

    Platelet aggregation and ATP-secretion induced by C. pneumoniae was markedly inhibited by the NO-donor S-nitroso-N-acetyl-d,l-penicillamine (SNAP), an effect that was counteracted by the guanylyl cyclase inhibitor 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ). Pre-treatment of platelets with the 12-lipoxygenase (12-LOX) inhibitors cinnamyl-3,4-dihydroxy-α-cyanocinnamate (CDC) and 5,6,7-trikydroxyflavone (baicalein) completely blocked the activation, whereas the cyclooxygenase (COX) inhibitors 2-acetyloxybenzoic acid (aspirin) and (8E)-8-[hydroxy-(pyridin-2-ylamino)methylidene]-9-methyl-10,10-dioxo-10$l^(6)thia-9-azabicyclo[4.4.0]deca-1,3,5-trien-7-one (piroxicam) had no inhibitory effects. Opposite to C. pneumoniae-induced activation, platelets stimulated by collagen were inhibited by the COX-inhibitors but were unaffected by the 12-LOX-inhibitors. The platelet activating factor (PAF) antagonist Ginkgolide B blocked the C. pneumoniae-induced platelet activation, whereas the responses to collagen were unaffected. Furthermore, the P2Y1 and P2Y12 purinergic receptor antagonists 2'-deoxy-N6-methyladenosine 3',5'-bisphosphate (MRS2179) and N(6)-(2-methyl-thioethyl)-2-(3,3,3-trifluoropropylthio)-beta,gamma-dichloromethylene-ATP (cangrelor) inhibited the aggregation and secretion caused by C. pneumoniae.

    It is well-known that the efficacy of COX inhibitors in the prevention and treatment of cardiovascular disease varies between different patients, and that patients with low responses to aspirin have a higher risk to encounter cardiovascular events. The findings in this study showing that platelets stimulated by C. pneumoniae are unaffected by COX inhibitors but sensitive to 12-LOX inhibitors, may thus be of importance in future management of atherosclerosis and thrombosis.

    Keywords
    Chlamydia pneumoniae, Platelet, Aggregation, Lipoxygenase, Cyclooxygenase
    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:liu:diva-14389 (URN)10.1016/j.ejphar.2007.03.024 (DOI)
    Available from: 2007-04-20 Created: 2007-04-20 Last updated: 2017-12-13Bibliographically approved
  • 7.
    Kälvegren, Hanna
    et al.
    Linköping University, Department of Medical and Health Sciences, Division of Cardiovascular Medicine. Linköping University, Faculty of Health Sciences.
    Andersson, Johanna
    Grenegård, Magnus
    Linköping University, Department of Medical and Health Sciences, Pharmacology. Linköping University, Faculty of Health Sciences.
    Bengtsson, Torbjörn
    Linköping University, Department of Medical and Health Sciences, Pharmacology. Linköping University, Faculty of Health Sciences.
    Platelet activation triggered by Chlamydia pneumoniae is antagonized by 12-lipoxygenase inhibitors but not cyclooxygenase inhibitors.2007In: European Journal of Pharmacology, ISSN 0014-2999, E-ISSN 1879-0712, Vol. 566, no 1-3, p. 20-27Article in journal (Refereed)
    Abstract [en]

    Chlamydia pneumoniae is a respiratory pathogen that has been linked to cardiovascular disease. We have recently shown that C. pneumoniae activates platelets, leading to oxidation of low-density lipoproteins. The aim of the present study was to evaluate the inhibitory effects of different pharmacological agents on platelet aggregation and secretion induced by C. pneumoniae.

    Platelet interaction with C. pneumoniae was studied by analyzing platelet aggregation and ATP-secretion with Lumi-aggregometry.

    Platelet aggregation and ATP-secretion induced by C. pneumoniae was markedly inhibited by the NO-donor S-nitroso-N-acetyl-d,l-penicillamine (SNAP), an effect that was counteracted by the guanylyl cyclase inhibitor 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ). Pre-treatment of platelets with the 12-lipoxygenase (12-LOX) inhibitors cinnamyl-3,4-dihydroxy-α-cyanocinnamate (CDC) and 5,6,7-trikydroxyflavone (baicalein) completely blocked the activation, whereas the cyclooxygenase (COX) inhibitors 2-acetyloxybenzoic acid (aspirin) and (8E)-8-[hydroxy-(pyridin-2-ylamino)methylidene]-9-methyl-10,10-dioxo-10$l^(6)thia-9-azabicyclo[4.4.0]deca-1,3,5-trien-7-one (piroxicam) had no inhibitory effects. Opposite to C. pneumoniae-induced activation, platelets stimulated by collagen were inhibited by the COX-inhibitors but were unaffected by the 12-LOX-inhibitors. The platelet activating factor (PAF) antagonist Ginkgolide B blocked the C. pneumoniae-induced platelet activation, whereas the responses to collagen were unaffected. Furthermore, the P2Y1 and P2Y12 purinergic receptor antagonists 2'-deoxy-N6-methyladenosine 3',5'-bisphosphate (MRS2179) and N(6)-(2-methyl-thioethyl)-2-(3,3,3-trifluoropropylthio)-beta,gamma-dichloromethylene-ATP (cangrelor) inhibited the aggregation and secretion caused by C. pneumoniae.

    It is well-known that the efficacy of COX inhibitors in the prevention and treatment of cardiovascular disease varies between different patients, and that patients with low responses to aspirin have a higher risk to encounter cardiovascular events. The findings in this study showing that platelets stimulated by C. pneumoniae are unaffected by COX inhibitors but sensitive to 12-LOX inhibitors, may thus be of importance in future management of atherosclerosis and thrombosis.

  • 8.
    Kälvegren, Hanna
    et al.
    Linköping University, Department of Medicine and Health Sciences, Pharmacology . Linköping University, Faculty of Health Sciences.
    Bylin, Helena
    Linköping University, Department of Clinical and Experimental Medicine, Occupational and Environmental Medicine . Linköping University, Faculty of Health Sciences.
    Leanderson, Per
    Linköping University, Department of Clinical and Experimental Medicine, Occupational and Environmental Medicine . Linköping University, Faculty of Health Sciences.
    Richter, Arina
    Linköping University, Department of Medicine and Health Sciences, Cardiology . Linköping University, Faculty of Health Sciences.
    Grenegård, Magnus
    Linköping University, Department of Medicine and Health Sciences, Pharmacology . Linköping University, Faculty of Health Sciences.
    Bengtsson, Torbjörn
    Linköping University, Department of Medicine and Health Sciences, Pharmacology . Linköping University, Faculty of Health Sciences.
    Chlamydia pneumoniae induces nitric oxide synthase and lipoxygenase-dependent production of reactive oxygen species in platelets — effects on oxidation of low-density lipoproteins.2005In: Thrombosis and Haemostasis, ISSN 0340-6245, Vol. 94, no 2, p. 327-335Article in journal (Refereed)
    Abstract [en]

    There is increasing evidence that Chlamydia pneumoniae is linked to atherosclerosis and thrombosis. In this regard, we have recently shown that C. pneumoniae stimulates platelet aggregation and secretion, which may play an important role in the progress of atherosclerosis and in thrombotic vascular occlusion. The aims of the present study were to investigate the effects of C. pneumoniae on platelet-mediated formation of reactive oxygen species (ROS) and oxidation of low-density lipoprotein (LDL) in vitro. ROS production was registered as changes in 2´,7`-dichlorofluorescin- fluorescence in platelets with flow cytometry. LDL-oxidation was determined by measuring thiobarbituric acid reactive substances (TBARs). We found that C. pneumoniae stimulated platelet production of ROS.Polymyxin B treatment of C. pneumoniae, but not elevated temperature, abolished the stimulatory effects on platelet ROS- production, which suggests that chlamydial lipopolysaccharide has an important role. In hibition of nitric oxide synthase with nitro-L-arginine, lipoxygenase with 5,8,11-eicosatriynoic acid and protein kinase C with GF 109203X significantly lowered the production of radicals. In contrast, inhibition of NADPH-oxidase with di-phenyleneiodonium (DPI) did not affect the C. pneumoniae induced ROS-production. These findings suggest that the activities of nitric oxide synthase and lipoxygenase are the sources for ROS and that the generation is dependent of the activity of protein kinase C.The C. pneumoniae-induced ROS-production in platelets was associated with an extensive oxidation of LDL, which was significantly higher compared to the effect obtained by separate exposure of LDL to C. pneumoniae or platelets. In conclusion, C. pneumoniae interaction with platelets leading to aggregation, ROS-production and oxidative damage on LDL, may play a crucial role in the development of atherosclerotic cardiovascular disease.

  • 9.
    Kälvegren, Hanna
    et al.
    Linköping University, Department of Medicine and Health Sciences, Pharmacology . Linköping University, Faculty of Health Sciences.
    Fridfeldt (Berggren), Jonna
    Linköping University, Department of Medicine and Health Sciences, Pharmacology . Linköping University, Faculty of Health Sciences.
    Garvin, Peter
    Linköping University, Department of Medicine and Health Sciences, Division of Preventive and Social Medicine and Public Health Science. Linköping University, Faculty of Health Sciences.
    Wind, Lena
    Leanderson, Per
    Linköping University, Department of Clinical and Experimental Medicine, Occupational and Environmental Medicine . Linköping University, Faculty of Health Sciences.
    Kristenson, Margaretha
    Linköping University, Department of Medicine and Health Sciences, Division of Preventive and Social Medicine and Public Health Science. Linköping University, Faculty of Health Sciences.
    Kihlström, Erik
    Linköping University, Department of Clinical and Experimental Medicine, Clinical Microbiology . Linköping University, Faculty of Health Sciences.
    Bengtsson, Torbjörn
    Linköping University, Department of Medicine and Health Sciences, Pharmacology . Linköping University, Faculty of Health Sciences.
    Richter, Arina
    Linköping University, Department of Medicine and Health Sciences, Cardiology . Linköping University, Faculty of Health Sciences.
    Correlation between rises in Chlamydia pneumoniae-specific antibodies, platelet activation and lipid peroxidation after percutaneous coronary intervention.2008In: European Journal of Clinical Microbiology and Infectious Diseases, ISSN 0934-9723, E-ISSN 1435-4373, Vol. 27, no 7, p. 503-511Article in journal (Refereed)
    Abstract [en]

    We recently showed that Chlamydia pneumoniae activates platelets in vitro, with an associated oxidation of low-density lipoproteins. The aim of this study was to investigate whether C. pneumoniae is released during percutaneous coronary intervention (PCI) and, thereby, causes platelet activation and lipid peroxidation. Seventy-three patients undergoing coronary angiography and following PCI or coronary artery bypass graft (CABG) and 57 controls were included in the study. C. pneumoniae antibodies, serotonin and lipid peroxidation were measured before and 24 h, 1 month and 6 months after angiography. The results show that serum C. pneumoniae IgA concentrations were significantly higher in patients than in the controls. Furthermore, in 38% of the C. pneumoniae IgG positive patients, the C. pneumoniae IgG concentration increased 1 month after PCI. The levels of C. pneumoniae IgG antibodies 1 month after PCI correlated with plasma-lipid peroxidation (r = 0.91, P < 0.0001) and platelet-derived serotonin (r = 0.62, P = 0.02). There was no elevation in the total serum IgG 1 month after PCI. In conclusion, the present results suggest that PCI treatment of coronary stenosis releases C. pneumoniae from the atherosclerotic lesions, which leads to platelet activation and lipid peroxidation.

  • 10.
    Kälvegren, Hanna
    et al.
    Linköping University, Department of Medical and Health Sciences, Division of Cardiovascular Medicine. Linköping University, Faculty of Health Sciences.
    Fridfeldt, Jonna
    Linköping University, Department of Medical and Health Sciences, Pharmacology. Linköping University, Faculty of Health Sciences.
    Bengtsson, Torbjörn
    Linköping University, Department of Medical and Health Sciences, Pharmacology. Linköping University, Faculty of Health Sciences.
    The role of plasma adenosine deaminase in chemoattractant-stimulated oxygen radical production in neutrophils2010In: EUROPEAN JOURNAL OF CELL BIOLOGY, ISSN 0171-9335, Vol. 89, no 6, p. 462-467Article in journal (Refereed)
    Abstract [en]

    Objectives: Adenosine deaminase (ADA) has a role in many immunity mediated disorders, such as asthma, tuberculosis and coronary artery disease. This study aims to investigate the ability of plasma ADA to modulate reactive oxygen species (ROS) production in neutrophils, and examine the involvement of adenosine and the cyclic AMP signaling pathway in this process. Methods: Neutrophils were stimulated, in the absence or presence of plasma, with the chemotactic peptide fMLP (formyl-methionyl-leucyl-phenylalanine), and the ROS production was determined with luminol-enhanced chemiluminescence. Activity of ADA was measured spectrophotometrically. Results: Plasma dose-dependently amplified the ROS generation in fMLP-stimulated neutrophils. In parallel, incubation of neutrophils in plasma elevated the total ADA-activity approximately 10 times from 1.3 U/ml to 12 U/ml. Inhibition of ADA, or type IV phosphodiesterases, significantly lowered the plasma-mediated ROS production. Furthermore, the high-affinity adenosine A(1) receptor antagonists DPCPX and 8-phenyltheophylline markedly inhibited the plasma-induced respiratory burst in neutrophils, suggesting an AI receptor-mediated mechanism. Conclusions: This study suggests that plasma ADA amplifies the release of toxic oxygen radicals from neutrophils through a downregulation of the inhibitory adenosine/cAMP-system and an enhanced activation of the stimulatory adenosine A(1)-receptor. This mechanism has probably a crucial role in regulating neutrophil function and in the defence against microbial infections. However, a sustained neutrophil activation could also contribute to inflammatory disorders such as atherosclerosis.

  • 11.
    Kälvegren, Hanna
    et al.
    Linköping University, Department of Medical and Health Sciences, Cardiology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Heart and Medicine Center, Department of Cardiology in Linköping. University of Örebro.
    Jonsson, Simon
    Jonasson, Lena
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Medical and Health Sciences, Division of Cardiovascular Medicine. Östergötlands Läns Landsting, Heart and Medicine Center, Department of Cardiology in Linköping.
    Release of matrix metalloproteinases-1 and-2, but not-9, from activated platelets measured by enzyme-linked immunosorbent assay2011In: Platelets, ISSN 0953-7104, E-ISSN 1369-1635, Vol. 22, no 8, p. 572-578Article in journal (Refereed)
    Abstract [en]

    Matrix metalloproteinases (MMPs), in particular MMP-9, have been introduced as novel biomarkers in coronary artery disease. Activated platelets are considered to be a major source of the highly elevated levels of MMPs that are detected in serum compared to plasma. The aim of this study was to clarify if activated platelets release MMPs-1, -2 and -9 as measured by enzyme-linked immunosorbent assays (ELISA). Isolated platelets (separated by several procedures) or platelet-rich plasma (PRP) were stimulated by collagen, thrombin or the TLR2 agonist Pam(3)CSK(4). The concentrations of MMPs-1,-2 and -9 in supernatants were determined by ELISA. In addition, a MMP-9 enzyme activity assay was used as well as immunofluorescent staining of MMPs-1,-2 and 9 in platelets. Isolated platelets stimulated by collagen, thrombin or Pam(3)CSK(4) released significant amounts of MMP-1 to the supernatant measured as either pro- or total-MMP-1. However, there was no detectable release of MMP-2 or -9 from isolated platelets. Collagen-stimulated platelets in PRP released MMP-2, but not -9. Before stimulation; platelets were positive for MMPs-1 and -2, but not -9, as assessed by immunofluorescence. Acting as positive controls, neutrophils were found to release significant amounts of MMP-9. Our findings indicate that activated platelets may be a major source of MMP-1 and to a minor extent MMP-2, in peripheral blood. However, in contrast to what has been argued in previous literature, platelets appear to be only negligible contributors to circulating MMP-9.

  • 12.
    Kälvegren, Hanna
    et al.
    Linköping University, Department of Medical and Health Sciences. Linköping University, Faculty of Health Sciences.
    Majeed, Meytham
    Linköping University, Department of health and environment.
    Bengtsson, Torbjörn
    Linköping University, Department of Medical and Health Sciences, Pharmacology. Linköping University, Faculty of Health Sciences.
    Chlamydia pneumoniae binds to platelets and triggers P-selectin expression and aggregation: A causal role in cardiovascular disease?2003In: Arteriosclerosis, Thrombosis and Vascular Biology, ISSN 1079-5642, E-ISSN 1524-4636, Vol. 23, no 9, p. 1677-1683Article in journal (Refereed)
    Abstract [en]

    Objective - Evidence linking Chlamydia pneumoniae to atherosclerotic cardiovascular disease is expanding. Platelets are considered to play an essential role in cardiovascular diseases, however, so far platelets have not been associated with an infectious cause of atherosclerosis. This study aims to clarify the interaction between Cpneumoniae and platelets and possibly present a novel mechanism in the pathogenesis of atherosclerosis.

    Methods and Results - The effects of C pneumoniae on platelet aggregation and secretion were assessed with lumiaggregometry, and the ability of C pneumoniae to bind to platelets and stimulate expression of P-selectin was analyzed with flow cytometry. We found that Cpneumoniae, at a chlamydia:platelet ratio of 1:15, adheres to platelets and triggers P-selectin expression after 1 minute and causes an extensive aggregation and ATP secretion after 20 minutes of incubation. Inhibition of glycoprotein IIb/IIIa with Arg-Gly-Asp-Ser or abciximab markedly reduced C pneumoniae-induced platelet aggregation. Exposure of C pneumoniae to polymyxin B, but not elevated temperature, abolished the stimulatory effects on platelet activation, suggesting that chlamydial lipopolysaccharide has an active role. In contrast, other tested bacteria had no or only moderate effects on platelet functions.

    Conclusion - Our findings demonstrate a new concept of how C pneumoniae activates platelets and thereby may cause atherosclerosis and thrombotic vascular occlusion.

     

  • 13.
    Kälvegren, Hanna
    et al.
    Linköping University, Department of Medical and Health Sciences, Division of Cardiovascular Medicine. Linköping University, Faculty of Health Sciences.
    Skoglund, Caroline
    Linköping University, Department of Medical and Health Sciences, Pharmacology. Linköping University, Faculty of Health Sciences.
    Helldahl, Christian
    Linköping University, Department of Medical and Health Sciences, Pharmacology. Linköping University, Faculty of Health Sciences.
    Lerm, Maria
    Linköping University, Department of Clinical and Experimental Medicine, Medical Microbiology. Linköping University, Faculty of Health Sciences.
    Grenegård, Magnus
    Linköping University, Department of Medical and Health Sciences, Pharmacology. Linköping University, Faculty of Health Sciences.
    Bengtsson, Torbjörn
    Linköping University, Department of Medical and Health Sciences, Pharmacology. Linköping University, Faculty of Health Sciences.
    Toll-like receptor 2 stimulation of platelets is mediated by purinergic P2X1-dependent Ca2+ mobilisation, cyclooxygenase and purinergic P2Y1 and P2Y12 receptor activation2010In: Thrombosis and Haemostasis, ISSN 0340-6245, Vol. 103, no 2, p. 398-407Article in journal (Refereed)
    Abstract [en]

    Toll-like receptor 2 (TLR2), which recognise and respond to conserved microbial pathogen-associated molecular patterns, is expressed on the platelet surface. Furthermore, it has recently been shown that the TLR2/1 agonist Pam(3)CSK(4) stimulates platelet activation. The aim of the present study was to clarify important signalling events in Pam(3)CSK(4)-induced platelet aggregation and secretion. Platelet interaction with Pam(3)CSK(4) and the TLR2/6 agonist MALP-2 was studied by analysing aggregation, ATP-secretion, [Ca2+](i) mobilisation and thromboxane B2 (TxB(2)) production. The results show that Pam(3)CSK(4) but not MALP-2 induces [Ca2+](i) increase, TxB(2) production, dense granule secretion and platelet aggregation. Preincubation of platelets with MALP-2 inhibited the Pam(3)CSK(4)-induced responses. The ATP-secretion and aggregation in Pam(3)CSK(4)-stimulated platelets was impeded by the purinergic P2X(1) inhibitor MRS 2159, the purinergic P2Y(1) and P2Y(12) antagonists MRS 2179 and cangrelor, the phospholipase C inhibitor U73122, the calcium chelator BAPT-AM and aspirin. The calcium mobilisation was lowered by MRS 2159, aspirin and U73122 whereas the TxB(2) production was antagonised by MRS 2159, aspirin and BAPT-AM. When investigating the involvement of the myeloid differentiation factor-88 (MyD88) -dependent pathway, we found that platelets express MyD88 and interleukin 1 receptor-associated kinase (IRAK-1), which are proteins important in TLR signalling. However, Pam(3)CSK(4) did not stimulate a rapid (within 10 minutes) phosphorylation of IRAK-1 in platelets. In conclusion, the results show that Pam(3)CSK(4)-induced platelet aggregation and secretion depends on a P2X(1)-mediated Ca2+ mobilisation, production of TxA(2) and ADP receptor activation. The findings in this study further support a role for platelets in sensing bacterial components.

  • 14.
    Lönn, J.
    et al.
    Division of Clinical Medicine, School of Health and Medical Sciences, Örebro University, Örebro, Sweden.
    Starkhammar Johansson, Carin
    Linköping University, Department of Medical and Health Sciences, Cardiology. Linköping University, Faculty of Health Sciences.
    Kälvegren, Hanna
    Linköping University, Department of Medical and Health Sciences, Cardiology. Linköping University, Faculty of Health Sciences.
    Brudin, Lars
    Linköping University, Department of Medical and Health Sciences, Clinical Physiology. Linköping University, Faculty of Health Sciences.
    Skoglund, Caroline
    Linköping University, Department of Physics, Chemistry and Biology, Molecular Surface Physics and Nano Science. Linköping University, The Institute of Technology.
    Garvin, Peter
    Linköping University, Department of Medical and Health Sciences, Social Medicine and Public Health Science. Linköping University, Faculty of Health Sciences.
    Särndahl, E.
    Department of Cardiology, Örebro University Hospital, Örebro, Sweden.
    Ravald, Nils
    Linköping University, Department of Medical and Health Sciences, Cardiology. Linköping University, Faculty of Health Sciences.
    Richter, Arina
    Linköping University, Department of Medical and Health Sciences, Cardiology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Heart and Medicine Center, Department of Cardiology in Linköping.
    Bengtsson, T.
    Division of Clinical Medicine, School of Health and Medical Sciences, Örebro University, Örebro, Sweden.
    Nayeri, Fariba
    Linköping University, Department of Clinical and Experimental Medicine, Infectious Diseases. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Heart and Medicine Center, Department of Infectious Diseases.
    Hepatocyte growth factor in patients with coronary artery disease and its relation to periodontal condition2012In: Results in Immunology, ISSN 2211-2839, Vol. 2, p. 7-12Article in journal (Refereed)
    Abstract [en]

    Hepatocyte growth factor (HGF) is an angiogenic, cardioprotective factor important for tissue and vascular repair. High levels of HGF are associated with chronic inflammatory diseases, such as coronary artery disease (CAD) and periodontitis, and are suggested as a marker of the ongoing atherosclerotic event in patients with CAD. Periodontal disease is more prevalent among patients with CAD than among healthy people. Recent studies indicate a reduced biological activity of HGF in different chronic inflammatory conditions. Biologically active HGF has high affinity to heparan sulfate proteoglycan (HSPG) on cell-membrane and extracellular matrix. The aim of the study was to investigate the serum concentration and the biological activity of HGF with ELISA and surface plasmon resonance (SPR), respectively, before and at various time points after percutaneous coronary intervention (PCI) in patients with CAD, and to examine the relationship with periodontal condition. The periodontal status of the CAD patients was examined, and the presence of P. gingivalis in periodontal pockets was analyzed with PCR. The HGF concentration was significantly higher, at all time-points, in patients with CAD compared to the age-matched controls (P< 0.001), but was independent of periodontal status. The HGF concentration and the affinity to HSPG adversely fluctuated over time, and the biological activity increased one month after intervention in patients without periodontitis. We conclude that elevated concentration of HGF but with reduced biological activity might indicate a chronic inflammatory profile in patients with CAD and periodontitis.

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