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Chlamydia pneumoniae induces nitric oxide synthase and lipoxygenase-dependent production of reactive oxygen species in platelets — effects on oxidation of low-density lipoproteins.
Linköping University, Department of Medicine and Health Sciences, Pharmacology . Linköping University, Faculty of Health Sciences.
Linköping University, Department of Clinical and Experimental Medicine, Occupational and Environmental Medicine . Linköping University, Faculty of Health Sciences.
Linköping University, Department of Clinical and Experimental Medicine, Occupational and Environmental Medicine . Linköping University, Faculty of Health Sciences.
Linköping University, Department of Medicine and Health Sciences, Cardiology . Linköping University, Faculty of Health Sciences.
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2005 (English)In: Thrombosis and Haemostasis, ISSN 0340-6245, Vol. 94, no 2, 327-335 p.Article 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.

Place, publisher, year, edition, pages
2005. Vol. 94, no 2, 327-335 p.
Keyword [en]
Atherosclerosis, bacteria-cell interaction, oxygen radical, LPS, thrombosis
National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:liu:diva-14387DOI: 10.1160/TH04-06-0360OAI: oai:DiVA.org:liu-14387DiVA: diva2:23382
Available from: 2007-04-20 Created: 2007-04-20
In thesis
1. The Role of Chlamydia pneumoniae-induced Platelet Activation in Cardiovascular Disease: In vitro and In vivo studies
Open this publication in new window or tab >>The Role of Chlamydia pneumoniae-induced Platelet Activation in Cardiovascular Disease: In vitro and In vivo studies
2007 (English)Doctoral 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.

Place, publisher, year, edition, pages
Institutionen för medicin och vård, 2007
Series
Linköping University Medical Dissertations, ISSN 0345-0082 ; 995
Keyword
Chlamydia pneumoniae, Platelet, atherosclerosis, Infection, LDL-oxidation, Percutaneous coronary intervention, Cardiovascular disease, Serotonin, Reactive oxygen species production
National Category
Pharmacology and Toxicology
Identifiers
urn:nbn:se:liu:diva-8643 (URN)978-91-85715-32-9 (ISBN)
Public defence
2007-05-11, Berzeliussalen, hus 420, Campus US, Linköpings universitet, Linköping, 09:00 (English)
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Available from: 2007-04-20 Created: 2007-04-20 Last updated: 2009-08-22

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Kälvegren, HannaLeanderson, PerRichter, ArinaGrenegård, MagnusBengtsson, Torbjörn

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