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  • 1.
    Bergström, Ida
    et al.
    Linköping University, Department of Medical and Health Sciences, Cardiology. Linköping University, Faculty of Health Sciences.
    Backteman, Karin
    Linköping University, Department of Clinical and Experimental Medicine, Clinical Immunology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Diagnostics, Department of Clinical Immunology and Transfusion Medicine.
    Lundberg, Anna
    Linköping University, Department of Medical and Health Sciences, Cardiology. Linköping University, Faculty of Health Sciences.
    Ernerudh, Jan
    Linköping University, Department of Clinical and Experimental Medicine, Clinical Immunology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Diagnostics, Department of Clinical Immunology and Transfusion Medicine.
    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.
    Persistent accumulation of interferon-gamma-producing CD8(+)CD56(+) T cells in blood from patients with coronary artery disease2012In: Atherosclerosis, ISSN 0021-9150, E-ISSN 1879-1484, Vol. 224, no 2, p. 515-520Article in journal (Refereed)
    Abstract [en]

    Objective: There is emerging evidence for CD8(+) T cell alterations in blood from patients with coronary artery disease (CAD). We examined whether the distribution and phenotype of CD8(+)CD56(+) T cells differed according to the clinical manifestation of CAD. less thanbrgreater than less thanbrgreater thanMethods: Patients with acute coronary syndrome (ACS, n = 30), stable angina (SA, n = 34) and controls (n = 36) were included. Blood was collected before and up to 12 months after referral for coronary investigation. CD8(+)CD56(+) T cells were assessed by flow cytometry for expression of surface markers, apoptosis, and intracellular expression of cytokines. less thanbrgreater than less thanbrgreater thanResults: The proportions of CD8(+)CD56(+) T cells were significantly higher in both ACS and SA patients compared with controls, and remained so after 3 and 12 months. This was independent of age, sex, systemic inflammation and cytomegalovirus seropositivity. CD8(+)CD56(+) T cells differed from CD8(+)CD56(-) T cells in terms of lower CD28 expression and fewer apoptotic cells. Both CD8(+) T cell subsets were positive for interferon (IFN)-gamma and tumor necrosis factor, although IFN-gamma was significantly more confined to the CD8(+)CD56(+) T cells. less thanbrgreater than less thanbrgreater thanConclusion: The persistent accumulation of CD8(+)CD56(+) T cells in ACS and SA patients share several features with immunological aging. It also contributes to a larger IFN-gamma(+) pool in blood, and may thereby hypothetically drive the atherosclerotic process in a less favorable direction.

  • 2. Cherfan, P
    et al.
    Tompa, A
    Wikby, A
    Löfgren, S
    Jonasson, Lena
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Medicine and Care, Cardiology. Östergötlands Läns Landsting, Heart Centre, Department of Cardiology.
    Effects of simvastatin on human T cells in vivo2007In: Atherosclerosis, ISSN 0021-9150, E-ISSN 1879-1484, Vol. 193, no 1, p. 186-192Article in journal (Refereed)
    Abstract [en]

    Objective: The use of statins has shown several anti-inflammatory actions, including modulatory effects on T cells in vitro. Since the effects on human T cells in vivo are less clarified, our aim was to investigate the effects of simvastatin on human T cells in vivo and ex vivo. Methods and results: A randomized, double-blind, placebo-controlled study design was applied. Eighty volunteers with mild to moderate hypercholesterolemia received either simvastatin 40 mg or placebo for 6 weeks. The serum levels of C-reactive protein (CRP) were significantly reduced by simvastatin. The proportions of CD4+ and CD8+ T cell subsets expressing early (CD25) or late (HLA-DR) activation markers, as assessed by flow cytometry, were not changed by simvastatin. However, simvastatin tended to increase the density of HLA-DR and L-selectin per CD8+ T cell. The T helper(h)1/Th2 response was evaluated by stimulatory assays followed by intra-cellular staining of interferon-γ and interleukin-4. Simvastatin treatment did not affect the Th1 response but the results indicated a potential to suppress Th2. Conclusion: Simvastatin treatment resulted in a few discrete changes as regards peripheral T cells. However, the findings do not provide evidence that simvastatin-induced anti-inflammatory actions are related to any significant modulatory effects on human T cells in clinically healthy men with hypercholesterolemia. © 2006 Elsevier Ireland Ltd. All rights reserved.

  • 3.
    Chung, Rosanna W S
    et al.
    Linköping University, Department of Medical and Health Sciences, Division of Cardiovascular Medicine. Linköping University, Faculty of Medicine and Health Sciences.
    Leandersson, Per
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Occupational and Environmental Medicine Center.
    Lundberg, Anna K
    Linköping University, Department of Medical and Health Sciences, Division of Cardiovascular Medicine. Linköping University, Faculty of Medicine and Health Sciences.
    Jonasson, Lena
    Linköping University, Department of Medical and Health Sciences, Division of Cardiovascular Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Department of Cardiology in Linköping.
    Lutein exerts anti-inflammatory effects in patients with coronary artery disease.2017In: Atherosclerosis, ISSN 0021-9150, E-ISSN 1879-1484, Vol. 262, p. 87-93, article id S0021-9150(17)30197-1Article in journal (Refereed)
    Abstract [en]

    BACKGROUND AND AIMS: Many coronary artery disease (CAD) patients exhibit chronic low-grade inflammation. Carotenoids are anti-oxidants with potential anti-inflammatory properties. Here, we first assessed relationships between interleukin (IL)-6 and individual carotenoids in plasma from CAD patients. Based on the results, we proceeded to assess anti-inflammatory effects of one carotenoid, lutein, in peripheral blood mononuclear cells (PBMCs) from CAD patients.

    METHODS: Lutein + zeaxanthin (isomers with lutein being dominant), β-cryptoxanthin, lycopene, α- and β-carotene and IL-6 were measured in plasma from 134 patients with stable angina (SA) and 59 patients with acute coronary syndrome. In 42 patients, plasma measurements were also performed 3 months after coronary intervention. PBMCs from SA patients were pre-treated with lutein (1, 5 and 25 μM) for 24 h followed by 24 h incubation ± lipopolysaccharide (LPS). Cell pellets were collected for IL-6, IL-1β and TNF mRNA and intracellular lutein. Cytokine secretion was measured in cell media.

    RESULTS: Only lutein + zeaxanthin were inversely correlated with IL-6 in SA patients at baseline (r = -0.366, p < 0.001) and follow-up (r = -0.546, p < 0.001). Ex vivo, lutein was taken up by PBMCs from SA patients in a dose- and time-dependent manner. Pre-treatment with lutein dose-dependently lowered LPS-induced secretion of IL-6, IL-1β (p < 0.01) and TNF (p < 0.05), and also reduced IL-6, IL-1β and TNF mRNA expression (p < 0.05).

    CONCLUSIONS: Clinical findings highlighted the inverse association between lutein and IL-6 in CAD patients. Anti-inflammatory effects of lutein in PBMCs from CAD patients were consolidated in ex vivo experiments. Taken together, these results show that lutein has the potential to play a role in resolution of chronic inflammation in CAD patients.

  • 4.
    Dziewierz, Artur
    et al.
    Jagiellonian University, Poland .
    Mielecki, Waldemar
    Jagiellonian University, Poland .
    Siudak, Zbigniew
    Jagiellonian University, Poland .
    Rakowski, Tomasz
    Jagiellonian University, Poland .
    Janzon, Magnus
    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.
    Birkemeyer, Ralf
    Schwarzwald Baar Klinikum, Germany .
    Zasada, Wojciech
    Jagiellonian University, Poland .
    Dubiel, Jacek S.
    Jagiellonian University, Poland .
    Dudek, Dariusz
    Jagiellonian University, Poland .
    Early abciximab administration before primary percutaneous coronary intervention improves clinical outcome in diabetic patients with ST-segment elevation myocardial infarction (EUROTRANSFER Registry)2012In: Atherosclerosis, ISSN 0021-9150, E-ISSN 1879-1484, Vol. 223, no 1, p. 212-218Article in journal (Refereed)
    Abstract [en]

    Background: Diabetes is an important determinant of prognosis in patients with ST-segment elevation myocardial infarction (STEMI). Limited data are available concerning benefits and risks of upstream abciximab administration in diabetic patients. Thus, the objective of the study was to assess the impact of early abciximab administration before primary angioplasty (PCI) for STEMI in diabetic patients. Methods: Data were gathered for 1650 consecutive STEMI patients transferred for primary PCI from hospital networks in seven countries in Europe from November 2005 to January 2007 (the EURO-TRANSFER Registry population). Patients were stratified by diabetes mellitus presence and then by abciximab administration strategy (early - more than 30 min before PCI vs. late). Results: Diabetes mellitus was diagnosed in 262 (15.9%) patients. Patients with diabetes mellitus were high-risk individuals, with advanced age, higher prevalence of comorbidities and increased risk of ischemic events during follow-up in comparison to non-diabetic patients. A total of 1086 patients who received abciximab were identified. Strategy of early abciximab administration was associated with enhanced infarct-related artery patency before PCI, and improved epicardial flow after PCI in both diabetic and non-diabetic patients. Importantly, early abciximab in diabetic patients led to the decrease in ischemic events, including 30-day (OR 0.260, 95% CI 0.089-0.759, p = 0.012) and 1-year (OR 0.273, 95% CI 0.099-0.749, p = 0.012) mortality reduction. However, only a trend toward improved survival was confirmed after adjustment for potential confounders. On the contrary, the reduction of 30-day (OR 0.620, 95% CI 0.334-1.189, p = 0.16) and 1-year (OR 0.643, 95% CI 0.379-1.089, p = 0.10) mortality rates was not significant among non-diabetic patients. Conclusions: Early administration of abciximab improves infarct-related artery patency before and after primary PCI, and leads to improved survival in diabetic STEMI patients.

  • 5.
    Hovland, Anders
    et al.
    Nordland Hospital, Norway; University of Tromso, Norway.
    Jonasson, Lena
    Linköping University, Department of Medical and Health Sciences, Division of Cardiovascular Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Department of Cardiology in Linköping.
    Garred, Peter
    Copenhagen University Hospital, Denmark.
    Yndestad, Arne
    National Hospital Norway, Norway; National Hospital Norway, Norway; University of Oslo, Norway.
    Aukrust, Pal
    National Hospital Norway, Norway; National Hospital Norway, Norway; University of Oslo, Norway.
    Lappegard, Knut T.
    Nordland Hospital, Norway; University of Tromso, Norway.
    Espevik, Terje
    Norwegian University of Science and Technology, Norway; Department Cancer Research and Molecular Med, Norway.
    Mollnes, Tom E.
    University of Tromso, Norway; University of Oslo, Norway; Norwegian University of Science and Technology, Norway; Department Cancer Research and Molecular Med, Norway; Nordland Hospital, Norway; National Hospital Norway, Norway; University of Oslo, Norway; University of Tromso, Norway.
    The complement system and toll-like receptors as integrated players in the pathophysiology of atherosclerosis2015In: Atherosclerosis, ISSN 0021-9150, E-ISSN 1879-1484, Vol. 241, no 2, p. 480-494Article, review/survey (Refereed)
    Abstract [en]

    Despite recent medical advances, atherosclerosis is a global burden accounting for numerous deaths and hospital admissions. Immune-mediated inflammation is a major component of the atherosclerotic process, but earlier research focus on adaptive immunity has gradually switched towards the role of innate immunity. The complement system and toll-like receptors (TLRs), and the crosstalk between them, may be of particular interest both with respect to pathogenesis and as therapeutic targets in atherosclerosis. Animal studies indicate that inhibition of C3a and C5a reduces atherosclerosis. In humans modified LDL-cholesterol activate complement and TLRs leading to downstream inflammation, and histopathological studies indicate that the innate immune system is present in atherosclerotic lesions. Moreover, clinical studies have demonstrated that both complement and TLRs are upregulated in atherosclerotic diseases, although interventional trials have this far been disappointing. However, based on recent research showing an intimate interplay between complement and TLRs we propose a model in which combined inhibition of both complement and TLRs may represent a potent anti-inflammatory therapeutic approach to reduce atherosclerosis. (C) 2015 The Authors. Published by Elsevier Ireland Ltd.

  • 6.
    Jacobsson, Leif
    et al.
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Medicine and Care, Pharmacology.
    Yuan, Xi Ming
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Neuroscience and Locomotion, Pathology.
    Ziedén, Bo
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Medicine and Care, Internal Medicine.
    Olsson, Anders G
    IMV Faculty ofHealth Sciences, Linköping.
    Effects of α-tocopherol and astaxanthin on LDL oxidation and atherosclerosis in WHHL rabbits2004In: Atherosclerosis, ISSN 0021-9150, E-ISSN 1879-1484, Vol. 173, no 2, p. 231-237Article in journal (Refereed)
    Abstract [en]

    The aim of this study was to evaluate the influence of α-tocopherol and astaxanthin on low-density lipoprotein (LDL) oxidation lag time and atherosclerotic lesion formation in Watanabe heritable hyperlipidemic (WHHL) rabbits. Thirty-one, 3-month-old WHHL rabbits were divided into three experimental groups. One group (n=10) was fed standard rabbit feed alone and served as a control, a second group (n=11) was supplied with the same feed containing 500mg α-tocopherol/kg and a third group (n=10) was given a feed containing 100mg astaxanthin/kg. Plasma lipids, lipoproteins and LDL oxidation lag time were followed for 24 weeks. At the end of the treatment period, the animals were killed and the thoracic aorta was used for evaluation of the degree of atherosclerosis. Colour photographs of the intimal surface of the vessel were taken for determination of the atherosclerotic area. Cross-sections of the thoracic aorta were used for histological examination and for determination of intimal thickening. Specimens of the vessel were used for determination of the tissue cholesterol content. Plasma cholesterol remained at a high level during the time of the experiment and there were no differences between the experimental groups. After 24 weeks, the LDL oxidation lag time was 53.7±1.7min, 109±4min (P<0.001) and 56.4±3.4min (P=0.47) in the control, α-tocopherol and astaxanthin groups, respectively. In the thoracic aorta, the atherosclerotic area was 80.7±5.1%, 67.1±6.7% (P=0.13) and 75.2±5.7% (P=0.49) in the control, α-tocopherol and astaxanthin groups, respectively. The intimal thickening was 45.6±3.2%, 44.0±4.1% (P=0.89) and 40.0±4.5% (P=0.33) in the control, α-tocopherol and astaxanthin groups, respectively. Finally, the cholesterol content was 107±9μmol/g, 95.7±11. 5μmol/g (P=0.31) and 101±5μmol/g (P=0.33) in the control, α-tocopherol and astaxanthin groups, respectively. It can be concluded that α-tocopherol but not astaxanthin prolonged the LDL oxidation lag time. The two antioxidative substances did not prevent atherogenesis in WHHL rabbits in this setting.

  • 7.
    Jonasson, Lena
    et al.
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Medicine and Care, Cardiology. Östergötlands Läns Landsting, Heart Centre, Department of Cardiology.
    Backteman, Karin
    Ernerudh, Jan
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Molecular and Clinical Medicine, Clinical Immunology. Östergötlands Läns Landsting, Centre for Laboratory Medicine, Department of Clinical Immunology and Transfusion Medicine.
    Loss of natural killer cell activity in patients with coronary artery disease2005In: Atherosclerosis, ISSN 0021-9150, E-ISSN 1879-1484, Vol. 183, no 2, p. 316-321Article in journal (Refereed)
    Abstract [en]

    Background:: Natural killer (NK) cells are important components of the innate immune system and have a potential role in the regulation of autoimmunity. In the present study, we evaluated the NK cells in patients with coronary artery disease (CAD) and related the findings to clinical and laboratory parameters of the disease. Methods and results:: We studied 45 patients with acute coronary syndrome (ACS), 50 patients with stable angina and angiographically verified CAD (SA) and 50 healthy controls. The distribution of NK cell subsets was determined by flow cytometry and NK cell-mediated cytotoxicity was quantified ex vivo. Both ACS and SA patients had significantly reduced numbers of CD56dim NK cells compared with controls. The patients also exhibited a significant decrease in NK cell activity. The loss in NK cell function was not related to inflammatory activity or metabolic status. Conclusion:: Both stable and unstable conditions of CAD were associated with a redistribution of circulating lymphocytes, comprising a significant reduction of CD56dim NK cells and a concomitant loss of NK cell function. The findings suggest the presence of a persistent immune aberration in CAD patients independent of their clinical setting or systemic inflammatory state. © 2005 Elsevier Ireland Ltd. All rights reserved.

  • 8.
    Jonasson, Lena
    et al.
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Medicine and Care, Cardiology. Östergötlands Läns Landsting, Heart Centre, Department of Cardiology.
    Ernerudh, Jan
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Molecular and Clinical Medicine, Clinical Immunology. Östergötlands Läns Landsting, Centre for Laboratory Medicine, Department of Clinical Immunology and Transfusion Medicine.
    Natural killer cells in coronary artery disease2004In: Atherosclerosis, ISSN 0021-9150, E-ISSN 1879-1484, Vol. 4, p. 312-312Article in journal (Refereed)
  • 9. Kervinen, H
    et al.
    Huittinen, T
    Vaarala, Outi
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Molecular and Clinical Medicine, Pediatrics. Östergötlands Läns Landsting, Centre of Paediatrics and Gynecology and Obstetrics, Barn.
    Leinonen, M
    Saikku, P
    Manninen, V
    Mänttäri, M
    Antibodies to human heat shock protein 60, hypertension and dyslipidemia. A study of joint effects on coronary risk.2003In: Atherosclerosis, ISSN 0021-9150, E-ISSN 1879-1484, Vol. 169, p. 339-344Article in journal (Refereed)
  • 10.
    Kinlay, Scott
    et al.
    Brigham & Womens Hospital.
    Schwartz, Gregory G
    Vet Affairs Med Centre.
    Olsson, Anders
    Linköping University, Department of Medical and Health Sciences, Internal Medicine. Linköping University, Faculty of Health Sciences.
    Rifai, Nader
    Harvard University.
    Bao, Weihang
    Pfizer Pharmaceuticals Group.
    Libby, Peter
    Brigham & Womens Hospital.
    Ganz, Peter
    San Francisco General Hospital.
    Endogenous tissue plasminogen activator and risk of recurrent cardiac events after an acute coronary syndrome in the MIRACL study2009In: Atherosclerosis, ISSN 0021-9150, E-ISSN 1879-1484, Vol. 206, no 2, p. 551-555Article in journal (Refereed)
    Abstract [en]

    Objective: To examine the relationship of baseline tissue plasminogen activator (t-PA) to early cardiovascular risk after an acute coronary syndrome, and the effect of intensive statin therapy. Methods: We measured plasma t-PA in 2860 of the 3086 (93%) subjects in the MIRACL study, an international randomized trial of atorvastatin 80mg daily versus placebo in patients with acute coronary syndromes. The relationship of t-PA to death, non-fatal acute myocardial infarction, cardiac arrest, or worsening angina over 16 weeks was assessed by Cox Proportional Hazards. D-dimer was measured in a random sample of 395 subjects. Results: Higher baseline t-PA was significantly related to the risk of recurrent events (HR = 1.25, p = 0.0014). This relationship was unaffected by adjustment for age, sex, troponin, hsCRP, and lipids (HR = 1.17, p = 0.029), but was attenuated by adjustment including body mass index and smoking (HR = 1.14, p = 0.08). D-dimer and t-PA concentrations were not related. Atorvastatin reduced the risk of recurrent events, but did not affect t-PA or D-dimer concentrations or the relationship of t-PA to outcomes. Conclusion: In patients with acute coronary syndromes, increasing t-PA concentration was related to a higher early risk of recurrent events, paradoxically reflecting impaired endogenous fibrinolysis. This relationship is due in part to the association of t-PA with age, body mass index and smoking. Although statins lower the risk of recurrent events after acute coronary syndromes, it is unlikely that this benefit is achieved through thrombolytic and fibrinolytic pathways. Published by Elsevier Ireland Ltd.

  • 11.
    Kristenson, Margareta
    et al.
    Linköping University, Faculty of Health Sciences. Linköping University, Department of health and environment. Östergötlands Läns Landsting, FHVC - Folkhälsovetenskapligt centrum, Förebygg.med.
    Lassvik, Claes
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Medicine and Care, Clinical Physiology. Östergötlands Läns Landsting, Heart Centre, Department of Clinical Physiology.
    Bergdahl, Björn
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Medicine and Care, Cardiology. Östergötlands Läns Landsting, Heart Centre, Department of Cardiology.
    Kucinskiene, Z
    Aizieniene, L
    Ziedén, Bo
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Medicine and Care, Internal Medicine. Östergötlands Läns Landsting, MKC-2, GE: endomed.
    Schäfer Elinder, Liselott
    Olsson, Anders
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Medicine and Care, Internal Medicine. Östergötlands Läns Landsting, MKC-2, GE: endomed.
    Ultrasound determined carotid and femoral atherosclerosis in Lithuanian and Swedish men: The LiVicordia study2000In: Atherosclerosis, ISSN 0021-9150, E-ISSN 1879-1484, Vol. 151, no 2, p. 501-508Article in journal (Refereed)
    Abstract [en]

    Coronary heart disease mortality is four times higher in Lithuanian compared to Swedish middle-aged men. Using the same equipment (Acuson XP10 with 5 MHz linear transducer) and staff, we compared the amount of atherosclerosis in carotid and femoral arteries in 100 randomly sampled 50-year-old men in each of the cities Vilnius, Lithuania and Linköping, Sweden. Atherosclerotic plaques were more abundant in Vilnius men compared to Linköping men (53 versus 28% in the common carotid artery, 73 versus 37% in the common femoral artery, P<0.001 for both). Plaques were thicker and more extended in arteries of Vilnius men, and an ultrasound atherosclerosis score was higher in both carotid and femoral arteries (P<0.001 for all). More Vilnius men had a maximal intima-media thickness of the common femoral artery above 1 mm (P<0.005). Stiffness in the common carotid artery was higher in Vilnius men (P<0.001). In a linear regression model of the pooled material, after adjustment for city was made, smoking, systolic blood pressure, low density lipoprotein cholesterol and β-carotene (inversely) significantly contributed to a high total ultrasound score (r2=0.32). These findings show that the higher coronary mortality noted in Lithuanian men goes together with a higher prevalence of early peripheral atherosclerosis.

  • 12.
    Li, Wei
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Health Sciences.
    Kornmark, Louise
    Linköping University, Department of Clinical and Experimental Medicine, Experimental Pathology. 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 Centre, Department of Cardiology.
    Forssell, Claes
    Linköping University, Department of Medical and Health Sciences, Vascular surgery. Linköping University, Faculty of Health Sciences.
    Yuan, Ximing
    Linköping University, Department of Medical and Health Sciences, Cardiology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Heart Centre, Department of Cardiology.
    Cathepsin L is significantly associated with apoptosis and plaque destabilization in human atherosclerosis2009In: Atherosclerosis, ISSN 0021-9150, E-ISSN 1879-1484, Vol. 202, no 1, p. 92-102Article in journal (Refereed)
    Abstract [en]

    Objective: Human atherosclerotic lesions overexpress elastolytic and collagenolytic cathepsins with unclear pathological implications. The aim of this study was to investigate the relationship among expression of cathepsin L. macrophage apoptosis in coronary artery disease (CAD) patients, clinical symptoms and plaque severity Of human carotid atheroma.

    Methods and results: Quantitative immunohistochemical analysis of human carotid atherosclerotic lesions (n = 49) showed that expression of lysosomal cathepsin L was significantly increased in atherosclerotic plaques with formation of the necrotic core and rupture of the cap. In those Plaques, cathepsin L was associated mainly with CD68-positive macrophages, whereas significant lower levels of smooth muscle cell actin were detected. The expression of cathepsin L in these plaques was also correlated with apoptosis and the stress protein ferritin. Plaques from symptomatic patients showed greater increased levels of cathepsin L than those front asymptomatic patients. Human monocyte-derived macrophages from CAD patients (n = 7) showed significantly higher levels of cathepsin L, cellular lipids and apoptosis versus cells from matched healthy donors (n = 7). 7Beta-hydroxycholesterol significantly enhanced cathepsin L in cells from healthy donors but not in Cells from CAD patients. Moreover. macrophage apoptosis was significantly correlated with expression of cathepsin L in cell nuclei and membranes.

    Conclusion: The results Suggest that cathepsin L is involved in death of macrophages necrotic Core formation and development of atherosclerotic plaque instability. Macrophage lysosomal cathepsin L and related apoptosis may be potential targets for modulation or imaging of vulnerable plaques in human atherosclerosis.

  • 13.
    Li, Wei
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Health Sciences.
    Lidebjer, Caroline
    Linköping University, Department of Medical and Health Sciences, Cardiology. Linköping University, Faculty of Health Sciences.
    Yuan, Ximing
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Experimental Pathology.
    Szymanowski, Aleksander
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Medical and Health Sciences, Cardiology. Östergötlands Läns Landsting, Heart Centre, Department of Cardiology.
    Backteman, Karin
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Clinical Immunology. Östergötlands Läns Landsting, Centre for Laboratory Medicine, Department of Clinical Immunology and Transfusion Medicine.
    Ernerudh, Jan
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Clinical Immunology. Östergötlands Läns Landsting, Centre for Laboratory Medicine, Department of Clinical Immunology and Transfusion Medicine.
    Leanderson, Per
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Occupational and Environmental Medicine. Östergötlands Läns Landsting, Pain and Occupational Centre, Occupational and Environmental Medicine Centre.
    Nilsson, Lennart
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Medicine and Care, Cardiology.
    Swahn, Eva
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Medical and Health Sciences, Cardiology. Östergötlands Läns Landsting, Heart Centre, Department of Cardiology.
    Jonasson, Lena
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Medical and Health Sciences, Cardiology. Östergötlands Läns Landsting, Heart Centre, Department of Cardiology.
    NK cell apoptosis in coronary artery disease. Relation to oxidative stress2008In: Atherosclerosis, ISSN 0021-9150, E-ISSN 1879-1484, Vol. 199, no 1, p. 65-72Article in journal (Refereed)
    Abstract [en]

    Objective: Natural killer (NK) cells, key elements in initiation and modulation of immune responses, were recently found to be reduced in coronary artery disease (CAD). To clarify mechanisms behind this reduction, we here investigated NK cell apoptosis in CAD patients. Since oxidative stress has been linked to NK cell apoptosis, we related the findings to oxidative stress in vivo and evaluated the ex vivo susceptibility of NK cells to oxidized lipids. Methods and results: The number of apoptotic NK cells in peripheral blood was significantly increased in CAD patients compared to controls. Purified NK cells from CAD patients also showed a higher rate of spontaneous apoptosis ex vivo. Dose- and time-dependent effects of oxidized LDL and 7β-hydroxycholesterol (7βOH) on apoptosis and ROS production were determined in NK cells from blood donors. Thereafter, purified NK cells from CAD patients and healthy controls were exposed to the oxidized lipids in a paired design. NK cells from patients were more susceptible to apoptosis induced by oxidized LDL, in particular 7βOH, compared to cells from controls. Plasma measurements of LDL protein oxidation and lipid peroxidation did not show any differences between patients and controls. On the other hand, plasma carotenoids were significantly decreased in patients and inversely correlated to NK cell apoptosis rate. Conclusion: The rate of spontaneous NK cell apoptosis was increased in CAD patients. Although NK cells in CAD patients were more sensitive to oxidized lipids ex vivo, indicating a mechanism contributing to the reduced NK cell activity in CAD, the data could not verify an obvious link between NK cell apoptosis and increased oxidative stress in vivo. © 2007 Elsevier Ireland Ltd. All rights reserved.

  • 14. Lindberg, G
    et al.
    Råstam, L
    Nilsson-Ehle, P
    Lundblad, Arne
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Biomedicine and Surgery, Clinical Chemistry. Östergötlands Läns Landsting, Centre for Laboratory Medicine, Department of Clinical Chemistry.
    Ranstam, J
    Folsom, AR
    Burke, GL
    Serum sialic acid and sialoglycoproteins in asymptomatic carotid artery atherosclerosis.1999In: Atherosclerosis, ISSN 0021-9150, E-ISSN 1879-1484, Vol. 146, p. 65-69Article in journal (Refereed)
  • 15.
    Lundberg, Anna
    et al.
    Linköping University, Department of Medical and Health Sciences, Division of Cardiovascular Medicine. Linköping University, Faculty of Medicine and Health Sciences.
    Jonasson, Lena
    Linköping University, Department of Medical and Health Sciences, Division of Cardiovascular Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Department of Cardiology in Linköping.
    Hansson, Göran K.
    Karolinska University Hospital, Sweden.
    Mailer, Reiner K. W.
    Karolinska University Hospital, Sweden.
    Activation-induced FOXP3 isoform profile in peripheral CD4+T cells is associated with coronary artery disease2017In: Atherosclerosis, ISSN 0021-9150, E-ISSN 1879-1484, Vol. 267, p. 27-33Article in journal (Refereed)
    Abstract [en]

    Background and aims: The expression of FOXP3 isoforms affects regulatory T (Treg) cell function. Reduced Treg cell function has been associated with coronary artery disease (CAD). However, alternative splicing of FOXP3 in CAD has not been investigated. Methods: FOXP3 splice variants and IL17A transcripts in peripheral blood mononuclear cells from stable CAD patients and healthy controls were quantified, and FOXP3 isoform expression in response to T cell receptor (TCR) stimulation or LDL was analyzed by flow cytometry. Results: Compared to healthy controls, CAD patients expressed significantly more FOXP3 transcripts that included exon 2, whereas alternative splicing of exon 7 in correlation with IL17A expression was reduced. Moreover, TCR stimulation, as well as exposure to LDL, decreased alternative splicing of FOXP3 in CD4+ T cells in vitro. Conclusions: Our results demonstrate that blood mononuclear cells in stable CAD patients express a ratio of FOXP3 isoforms that is characteristic for activated CD4+ T cells. (C) 2017 Elsevier B.V. All rights reserved.

  • 16.
    Nielsen, Niels Erik
    et al.
    Linköping University, Department of Medicine and Care, Cardiology. Linköping University, Faculty of Health Sciences.
    Brattström, Lars
    Department of Medicine, County Hospital, Kalmar, Sweden.
    Hultberg, Björn
    Department of Clinical Chemistry, University Hospital, Lund, Sweden.
    Landgren, Finn
    Department of Medicine, County Hospital, Kalmar, Sweden.
    Swahn, Eva
    Linköping University, Department of Medicine and Care, Cardiology. Linköping University, Faculty of Health Sciences.
    Plasma total homocysteine levels in postmenopausal women with unstable coronary artery disease2000In: Atherosclerosis, ISSN 0021-9150, E-ISSN 1879-1484, Vol. 151, no 2, p. 423-431Article in journal (Refereed)
    Abstract [en]

    An elevated plasma total homocysteine (tHcy) level is considered a risk factor for coronary artery disease (CAD), but the relationship between plasma tHcy and well-defined CAD in women is still unclear. Plasma tHcy concentrations and the covariates serum folate, vitamin B12, and creatinine were analysed in 157 angiographically examined postmenopausal women with unstable CAD and in 101 healthy controls. At coronary angiography, 16% had normal vessels and 84% had coronary atherosclerosis. Mean plasma tHcy concentration (μmol/l, 95% confidence interval) did not differ in patients compared to controls (13.1 (12.3–13.8) vs. 12.5 (11.6–13.5)) or in patients with or without coronary atherosclerosis (13.3 (12.4–14.1) vs. 12.0 (10.8–13.2)). A trend to an increasing plasma tHcy with increasing degree of coronary atherosclerosis was attenuated after adjustment for age and the previous mentioned covariates. Odds ratio for the risk of coronary artery disease and coronary atherosclerosis in hyperhomocysteinemic patients (≥90th percentile in controls) was approximately 3. However, the confidence interval included unity in half of the groups and the significance was therefore difficult to judge. Receiver operating characteristics showed age to be the only variable with a significant discriminatory ability regarding the presence of coronary atherosclerosis (area 0.77). Mild hyperhomocysteinemia seems not to be related to the risk of unstable CAD in postmenopausal women. The trend towards higher plasma tHcy with increasing degree of coronary atherosclerosis may be a marker of the disease. In future studies adjustment for age and the other three covariates should be considered.

  • 17.
    Olsson, Anders
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Medicine and Care, Internal Medicine. Östergötlands Läns Landsting, Centre for Medicine, Department of Endocrinology and Gastroenterology UHL.
    Lipoprotein Changes and Reduction in the Incidence of Major Coronary Heart Disease Events in teh Scandinavian Simvastatin Survival Study2004In: Atherosclerosis, ISSN 0021-9150, E-ISSN 1879-1484, Vol. 5, p. 99-106Article in journal (Refereed)
  • 18.
    Olsson, Anders
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Medicine and Care, Internal Medicine. Östergötlands Läns Landsting, Centre for Medicine, Department of Endocrinology and Gastroenterology UHL.
    The importance of the emergence of statins toa lipidologist - clinician: a personal perspective2004In: Atherosclerosis, ISSN 0021-9150, E-ISSN 1879-1484, Vol. 5, p. 27-28Article in journal (Refereed)
  • 19. Sheikine, Y
    et al.
    Bang, CS
    Nilsson, Lennart
    Linköping University, Department of Medicine and Care. Linköping University, Faculty of Health Sciences.
    Samnegård, A
    Hamsten, A
    Jonasson, Lena
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Medicine and Care, Cardiology. Östergötlands Läns Landsting, Heart Centre, Department of Cardiology.
    Eriksson, P
    Sirsjö, A
    Decreased plasma CXCL16/SR-PSOX concentration is associated with coronary artery disease2006In: Atherosclerosis, ISSN 0021-9150, E-ISSN 1879-1484, Vol. 188, no 2, p. 462-466Article in journal (Refereed)
    Abstract [en]

    Objectives: To investigate for the first time whether the plasma CXCL16 concentration is altered in coronary artery disease (CAD) patients. Background: Accumulating evidence suggests that the novel chemokine/scavenger receptor CXCL16/SR-PSOX is involved in the development of atherosclerosis and CAD. Methods: Using ELISA we assessed the plasma CXCL16 concentration in 40 stable angina pectoris (SAP) patients, 17 unstable angina pectoris/non-ST-elevation myocardial infarction (UAP/non-STEMI) patients, 387 survivors of a first myocardial infarction (MI) and healthy control subjects (44 controls for SAP and UAP/non-STEMI patient groups and 387 controls for post-MI patients). Results: SAP patients exhibited significantly lower median CXCL16 levels (2111 pg/ml) than the corresponding control subjects (2678 pg/ml) (P = 0.0012). UAP/non-STEMI patients also appeared to have lower CXCL16 levels (2192 pg/ml) compared with controls (NS). Patients investigated 3 months after MI tended (P = 0.07) to have lower CXCL16 levels (2529 pg/ml) than the corresponding controls (2638 pg/ml). There were no significant correlations between CXCL16 levels and different measures of CAD severity determined by quantitative coronary angiography in post-MI patients. Neither patients nor controls exhibited significant correlations between CXCL16 levels and plasma lipoprotein fractions, inflammatory cytokines, C-reactive protein or numbers of inflammatory cells in peripheral blood. Conclusions: The finding that lower plasma CXCL16 concentration is associated with CAD might indicate a potential atheroprotective function of CXCL16. © 2005 Elsevier Ireland Ltd. All rights reserved.

  • 20.
    Szymanowski, Aleksander
    et al.
    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.
    Li, Wei
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Health Sciences.
    Lundberg, Anna
    Linköping University, Department of Medical and Health Sciences, Division of Cardiovascular Medicine. Linköping University, Faculty of Health Sciences.
    Evaldsson, Chamilly
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Center for Diagnostics, Department of Clinical Chemistry.
    Nilsson, Lennart
    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.
    Backteman, Karin
    Linköping University, Department of Clinical and Experimental Medicine, Division of Inflammation Medicine. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Center for Diagnostics, Department of Clinical Immunology and Transfusion Medicine.
    Ernerudh, Jan
    Linköping University, Department of Clinical and Experimental Medicine, Division of Inflammation Medicine. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Center for Diagnostics, Department of Clinical Immunology and Transfusion Medicine.
    Jonasson, Lena
    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.
    Soluble Fas ligand is associated with natural killer cell dynamics in coronary artery disease2014In: Atherosclerosis, ISSN 0021-9150, E-ISSN 1879-1484, Vol. 233, no 2, p. 616-622Article in journal (Refereed)
    Abstract [en]

    Objective: Apoptosis of natural killer (NK) cells is increased in patients with coronary artery disease (CAD) and may explain why NK cell levels are altered in these patients. Soluble forms of Fas and Fas ligand (L) are considered as markers of apoptosis. Here, we investigated whether plasma levels of Fas and FasL were associated with NK cell apoptosis and NK cell levels in CAD patients. Methods: Fas and FasL in plasma were determined by ELISA in 2 cohorts of CAD patients; one longitudinal study measuring circulating NK cells and apoptotic NK cells by flow cytometry 1 day, 3 months and 12 months after a coronary event and one cross-sectional study measuring NK cell apoptosis ex vivo. Both studies included matched healthy controls. Fas and FasL were also determined in supernatants from NK cells undergoing cytokine-induced apoptosis in cell culture. Results: In the 12-month longitudinal study, plasma FasL increased by 15% (p less than 0.001) and NK cell levels by 31% (p less than 0.05) while plasma Fas did not change. Plasma FasL and NK cell levels were significantly related at 3 months and 12 months, r = 0.40, p less than 0.01. Furthermore, plasma FasL, but not plasma Fas, correlated with NK cell apoptosis ex vivo in CAD patients, r = 0.54, p less than 0.05. In vitro, cytokine-induced apoptosis of NK cells resulted in abundant release of FasL. Conclusion: In CAD patients, FasL in plasma is associated with both apoptotic susceptibility of NK cells and dynamic changes in circulating NK cells. NK cells are also themselves a potential source of soluble FasL. Our findings link NK cell status to a soluble marker with possible atheroprotective effects thereby supporting a beneficial role of NK cells in CAD.

  • 21.
    Vallejo-Vaz, Antonio J.
    et al.
    Imperial Coll London, England.
    De Marco, Martina
    Imperial Coll London, England.
    Stevens, Christophe A. T.
    Imperial Coll London, England.
    Akram, Asif
    Living Goods, Kenya.
    Freiberger, Tomas
    Ctr Cardiovasc Surg and Transplantat, Czech Republic; Masaryk Univ, Czech Republic.
    Hovingh, G. Kees
    Acad Med Ctr, Netherlands.
    Kastelein, John J. P.
    Acad Med Ctr, Netherlands.
    Mata, Pedro
    Fdn Hipercolesterolemia Familiar, Spain.
    Raal, Frederick J.
    Univ Witwatersrand, South Africa.
    Santos, Raul D.
    Univ Sao Paulo, Brazil; Hosp Israelita Albert Einstein, Brazil.
    Soran, Handrean
    Manchester Univ Hosp NHS Fdn Trust, England.
    Watts, Gerald F.
    Univ Western Australia, Australia; Royal Perth Hosp, Australia; FH Australasia Network FHAN, Australia.
    Abifadel, Marianne
    St Joseph Univ, Lebanon.
    Aguilar-Salinas, Carlos A.
    Inst Nacl Ciencias Med and Nutr Salvador Zubiran, Mexico.
    Al-Khnifsawi, Mutaz
    Al Qadisiyah Univ, Iraq.
    AlKindi, Fahad A.
    Hamad Med Corp, Qatar.
    Alnouri, Fahad
    Prince Sultan Cardiac Ctr Riyadh, Saudi Arabia.
    Alonso, Rodrigo
    Clin Las Condes, Chile.
    Al-Rasadi, Khalid
    Sultan Qaboos Univ Hosp, Oman.
    Al-Sarraf, Ahmad
    Kuwait Canc Control Ctr, Kuwait.
    Ashavaid, Tester F.
    PD Hinduja Natl Hosp and Med Res Ctr, India.
    Binder, Christoph J.
    Med Univ Vienna, Austria.
    Bogsrud, Martin P.
    Oslo Univ Hosp, Norway; Oslo Univ Hosp, Norway.
    Bourbon, Mafalda
    Inst Nacl Saude Doutor Ricardo Jorge, Portugal; Univ Lisbon, Portugal.
    Bruckert, Eric
    Hop La Pitie Salpetriere, France; Hop La Pitie Salpetriere, France.
    Chlebus, Krzysztof
    Med Univ Gdansk, Poland; Univ Clin Ctr, Poland.
    Corral, Pablo
    FASTA Univ, Argentina.
    Descamps, Olivier
    Ctr Hosp Jolimont, Belgium.
    Durst, Ronen
    Hadassah Hebrew Univ Med Ctr, Israel; Hadassah Hebrew Univ Med Ctr, Israel.
    Ezhov, Marat
    Minist Hlth Russian Federat, Russia.
    Fras, Zlatko
    Univ Med Ctr Ljubljana, Slovenia; Univ Ljubljana, Slovenia.
    Genest, Jacques
    McGill Univ, Canada.
    Groselj, Urh
    Univ Med Ctr Ljubljana, Slovenia.
    Harada-Shiba, Mariko
    Natl Cerebral and Cardiovasc Ctr, Japan.
    Kayikcioglu, Meral
    Ege Univ, Turkey.
    Lalic, Katarina
    Univ Belgrade, Serbia; Clin Ctr Serbia, Serbia.
    Lam, Carolyn S. P.
    Natl Heart Ctr, Singapore; Duke NUS Med Sch, Singapore.
    Latkovskis, Gustavs
    Univ Latvia, Latvia.
    Laufs, Ulrich
    Univ Klinikum Leipzig, Germany.
    Liberopoulos, Evangelos
    Univ Ioannina, Greece.
    Lin, Jie
    Capital Med Univ, Peoples R China.
    Maher, Vincent
    Adv Lipid Management and Res ALMAR Ctr, Ireland.
    Majano, Nelson
    Hosp Mil Caracas, Venezuela.
    Marais, A. David
    Univ Cape Town, South Africa; Natl Hlth Lab Serv, South Africa.
    Maerz, Winfried
    Heidelberg Univ, Germany; Med Univ Graz, Austria; Synlab Holding Deutschland GmbH, Germany; Synlab Holding Deutschland GmbH, Germany; D A CH Gesell Pravent Herz Kreislauf Erkrankungen, Germany.
    Mirrakhimov, Erkin
    Kyrgyz State Med Acad, Kyrgyzstan.
    Miserez, Andre R.
    Swiss FH Ctr, Switzerland; Univ Basel, Switzerland.
    Mitchenko, Olena
    Natl Acad Med Sci Ukraine, Ukraine.
    Nawawi, Hapizah M.
    Inst Pathol Lab and Forens Med I PPerForM, Malaysia; Univ Teknol Malaysia, Malaysia.
    Nordestgaard, Borge G.
    Copenhagen Univ Hosp, Denmark; Copenhagen Univ Hosp, Denmark; Univ Copenhagen, Denmark.
    Paragh, Gyorgy
    Univ Debrecen, Hungary.
    Petrulioniene, Zaneta
    Vilnius Univ, Lithuania; Vilnius Univ Hosp Santaros Klin, Lithuania.
    Pojskic, Belma
    Cantonal Hosp Zenica, Bosnia and Herceg.
    Postadzhiyan, Arman
    Med Univ Sofia, Bulgaria.
    Reda, Ashraf
    Menoufia Univ, Egypt; Egyptian Assoc Vernacular Biol and Atherosclerosis, Egypt.
    Reiner, Zeljko
    Univ Zagreb, Croatia.
    Sadoh, Wilson E.
    Univ Benin, Nigeria.
    Sahebkar, Amirhossein
    Mashhad Univ Med Sci, Iran; Mashhad Univ Med Sci, Iran; Mashhad Univ Med Sci, Iran.
    Shehab, Abdullah
    United Arab Emirates Univ, U Arab Emirates.
    Shek, Aleksander B.
    Minist Hlth Republ Uzbekistan, Uzbekistan.
    Stoll, Mario
    Honorary Commiss Cardiovasc Hlth CHSCV, Uruguay.
    Su, Ta-Chen
    Natl Taiwan Univ Hosp, Taiwan.
    Subramaniam, Tavintharan
    Admiralty Med Ctr, Singapore; Khoo Teck Puat Hosp, Singapore; Khoo Teck Puat Hosp, Singapore.
    Susekov, Andrey V.
    Acad Postgrad Med Educ, Russia; Acad Med Sci, Russia.
    Symeonides, Phivos
    Hippocrateon Private Hosp, Cyprus.
    Tilney, Myra
    Univ Malta, Malta; Mater Dei Hosp, Malta.
    Tomlinson, Brian
    Chinese Univ Hong Kong, Peoples R China.
    Thanh-Huong, Truong
    Hanoi Med Univ, Vietnam; Bach Mai Hosp, Vietnam.
    Tselepis, Alexandros D.
    Univ Ioannina, Greece.
    Tybjaerg-Hansenb, Anne
    Copenhagen Univ Hosp, Denmark; Copenhagen Univ Hosp, Denmark; Univ Copenhagen, Denmark; Copenhagen Univ Hosp, Denmark.
    Vazquez-Cardenas, Alejandra
    Univ Autonoma Guadalajara, Mexico.
    Viigimaa, Margus
    Tallinn Univ Technol, Estonia.
    Vohnout, Branislav
    Slovak Med Univ, Slovakia.
    Widen, Elisabeth
    Univ Helsinki, Finland.
    Yamashita, Shizuya
    Rinku Gen Med Ctr, Japan; Osaka Univ, Japan.
    Banach, Maciej
    Med Univ Lodz, Poland.
    Gaita, Dan
    Univ Med and Farm Victor Babes Timisoara, Romania.
    Jiang, Lixin
    Natl Ctr Cardiovasc Dis, Peoples R China.
    Nilsson, Lennart
    Linköping University, Department of Medical and Health Sciences, Division of Cardiovascular Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Department of Cardiology in Linköping.
    Santos, Lourdes E.
    Univ Philippines, Philippines.
    Schunkert, Heribert
    Tech Univ Munich, Germany.
    Tokgozoglu, Lale
    Hacettepe Univ, Turkey.
    Car, Josip
    Imperial Coll London, England; Nanyang Technol Univ, Singapore.
    Catapano, Alberico L.
    Univ Milan, Italy; IRCCS MultiMed, Italy.
    Ray, Kausik K.
    Imperial Coll London, England.
    Overview of the current status of familial hypercholesterolaemia care in over 60 countries - The EAS Familial Hypercholesterolaemia Studies Collaboration (FHSC)2018In: Atherosclerosis, ISSN 0021-9150, E-ISSN 1879-1484, Vol. 277, p. 234-255Article in journal (Refereed)
    Abstract [en]

    Background and aims: Management of familial hypercholesterolaemia (FH) may vary across different settings due to factors related to population characteristics, practice, resources and/or policies. We conducted a survey among the worldwide network of EAS FHSC Lead Investigators to provide an overview of FH status in different countries. Methods: Lead Investigators from countries formally involved in the EAS FHSC by mid-May 2018 were invited to provide a brief report on FH status in their countries, including available information, programmes, initiatives, and management. Results: 63 countries provided reports. Data on FH prevalence are lacking in most countries. Where available, data tend to align with recent estimates, suggesting a higher frequency than that traditionally considered. Low rates of FH detection are reported across all regions. National registries and education programmes to improve FH awareness/knowledge are a recognised priority, but funding is often lacking. In most countries, diagnosis primarily relies on the Dutch Lipid Clinics Network criteria. Although available in many countries, genetic testing is not widely implemented (frequent cost issues). There are only a few national official government programmes for FH. Under-treatment is an issue. FH therapy is not universally reimbursed. PCSK9-inhibitors are available in similar to 2/3 countries. Lipoprotein-apheresis is offered in similar to 60% countries, although access is limited. Conclusions: FH is a recognised public health concern. Management varies widely across countries, with overall suboptimal identification and under-treatment. Efforts and initiatives to improve FH knowledge and management are underway, including development of national registries, but support, particularly from health authorities, and better funding are greatly needed.

  • 22.
    Vallejo-Vaz, Antonio J.
    et al.
    University of London Imperial Coll Science Technology and Med, England.
    Rao Kondapally Seshasai, Sreenivasa
    St Georges University of London, England.
    Kees Della Cole; Hovingh, G.
    Not Found:[Vallejo-Vaz, Antonio J.; Ray, Kausik K.] Univ London Imperial Coll Sci Technol and Med, Sch Publ Hlth, London, England; [Seshasai, Sreenivasa Rao Kondapally; Della Cole] St Georges Univ London, Cardiovasc and Cell Sci Res Inst, London, England; [Hovingh, G. Kees; Kastelein, John J. P.] Univ Amsterdam, Acad Med Ctr, NL-1105 AZ Amsterdam, Netherlands; [Mata, Pedro] Fdn Hipercolesterolemia Familiar, Madrid, Spain; [Raal, Frederick J.] Univ Witwatersrand, Fac Hlth Sci, Johannesburg, South Africa; [Santos, Raul D.] Univ Sao Paulo, Med Sch Hosp, Heart Inst InCor, Sao Paulo, Brazil; [Soran, Handrean] Univ Manchester, Fac Med and Hlth Sci, Manchester, Lancs, England; [Watts, Gerald F.] Univ Western Australia, Royal Perth Hosp, Cardiovasc Med, Perth, WA 6009, Australia; [Abifadel, Marianne] St Joseph Univ, Fac Pharm, Lab Biochem and Mol Therapeut, Beirut, Lebanon; [Aguilar-Salinas, Carlos A.] Inst Nacl Ciencias Med and Nutr Salvador Zubiran, Mexico City, DF, Mexico; [Akram, Asif; Car, Josip] Univ London Imperial Coll Sci Technol and Med, Sch Publ Hlth, Global eHlth Unit, London, England; [Alnouri, Fahad] Prince Sultan Cardiac Ctr Riyadh, Cardiovasc Prevent and Rehabil Unit, Riyadh, Saudi Arabia; [Alonso, Rodrigo] Lipid Clin, Dept Nutr, Clin Condes, Santiago, Chile; [Al-Rasadi, Khalid] Sultan Qaboos Univ Hosp, Muscat, Oman; [Banach, Maciej] Med Univ Lodz, Dept Hypertens, Lodz, Poland; [Bogsrud, Martin P.] Natl Advisory Unit Familial Hypercholesterolemia, Oslo, Norway; [Bourbon, Mafalda] Univ Lisbon, Inst Nacl Saude Doutor Ricardo Jorge and BioISI, Biosyst and Integrat Sci Inst, P-1699 Lisbon, Portugal; [Bruckert, Eric] Hop La Pitie Salpetriere, Endocrinol Metab and Prevent Cardiovasc, Inst and IHU Cardiometab ICAN E3M, Paris, France; [Car, Josip] Nanyang Technol Univ, Lee Kong Chian Sch Med, Singapore 639798, Singapore; [Corral, Pablo] FASTA Univ, Sch Med, Mar Del Plata, Buenos Aires, Argentina; [Descamps, Olivier] Hop Jolimont, Haine St Paul, Belgium; [Dieplinger, Hans] Med Univ Innsbruck, Austrian Atherosclerosis Soc, A-6020 Innsbruck, Austria; [Durst, Ronen] Hadassah Hebrew Univ, Med Ctr, Jerusalem, Israel; [Freiberger, Tomas] Masaryk Univ, Ctr Cardiovasc Surg and Transplantat Brno and Ceitec, Brno, Czech Republic; [Gaspar, Isabel M.] Univ Lisbon, Lisbon Med Sch, Ctr Hosp Lisboa Ocidental and Genet Lab, Dept Med Genet, P-1699 Lisbon, Portugal; [Genest, Jaques] McGill Univ, Montreal, PQ, Canada; [Harada-Shiba, Mariko] Natl Cerebral and Cardiovasc Ctr Res Inst, Osaka, Japan; [Jiang, Lixin] Natl Ctr Cardiovasc Dis, Beijing, Peoples R China; [Kayikcioglu, Meral] Ege Univ, Sch Med, Dept Cardiol, Izmir, Turkey; [Lam, Carolyn S. P.] Natl Heart Ctr Singapore, Singapore, Singapore; [Lam, Carolyn S. P.] Duke Natl Univ Singapore, Singapore, Singapore; [Latkovskis, Gustavs] Univ Latvia, Latvian Res Inst Cardiol, Paul Stradins Clin Univ Hosp, Riga, Latvia; [Laufs, Ulrich] Univ Saarland, Homburg, Germany; [Liberopoulos, Evangelos] Univ Ioannina, Sch Med, GR-45110 Ioannina, Greece; [Nilsson, Lennart] Linkoping Univ, Dept Med and Hlth Sci, Linkoping, Sweden; [Nordestgaard, Borge G.] Univ Copenhagen, Copenhagen Univ Hosp, Herlev and Gentofte Hosp, Copenhagen, Denmark.
    Kastelein, John J. P.
    University of Amsterdam, Netherlands.
    Mata, Pedro
    Fdn Hipercolesterolemia Familiar, Spain.
    Raal, Frederick J.
    University of Witwatersrand, South Africa.
    Santos, Raul D.
    University of Sao Paulo, Brazil.
    Soran, Handrean
    University of Manchester, England.
    Watts, Gerald F.
    University of Western Australia, Australia.
    Abifadel, Marianne
    St Joseph University, Lebanon.
    Aguilar-Salinas, Carlos A.
    Institute Nacl Ciencias Medical and Nutr Salvador Zubiran, Mexico.
    Akram, Asif
    University of London Imperial Coll Science Technology and Med, England.
    Alnouri, Fahad
    Prince Sultan Cardiac Centre Riyadh, Saudi Arabia.
    Alonso, Rodrigo
    Lipid Clin, Chile.
    Al-Rasadi, Khalid
    Sultan Qaboos University Hospital, Oman.
    Banach, Maciej
    Medical University of Lodz, Poland.
    Bogsrud, Martin P.
    National Advisory Unit Familial Hypercholesterolemia, Norway.
    Bourbon, Mafalda
    University of Lisbon, Portugal.
    Bruckert, Eric
    Hop La Pitie Salpetriere, France.
    Car, Josip
    University of London Imperial Coll Science Technology and Med, England; Nanyang Technology University, Singapore.
    Corral, Pablo
    FASTA University, Argentina.
    Descamps, Olivier
    Hop Jolimont, Belgium.
    Dieplinger, Hans
    Medical University of Innsbruck, Austria.
    Durst, Ronen
    Hadassah Hebrew University, Israel.
    Freiberger, Tomas
    Masaryk University, Czech Republic.
    Gaspar, Isabel M.
    University of Lisbon, Portugal.
    Genest, Jaques
    McGill University, Canada.
    Harada-Shiba, Mariko
    National Cerebral and Cardiovasc Centre Research Institute, Japan.
    Jiang, Lixin
    National Centre Cardiovasc Disease, Peoples R China.
    Kayikcioglu, Meral
    Ege University, Turkey.
    Lam, Carolyn S. P.
    National Heart Centre Singapore, Singapore; Duke National University of Singapore, Singapore.
    Latkovskis, Gustavs
    University of Latvia, Latvia.
    Laufs, Ulrich
    University of Saarland, Germany.
    Liberopoulos, Evangelos
    University of Ioannina, Greece.
    Nilsson, Lennart
    Linköping University, Department of Medical and Health Sciences, Division of Cardiovascular Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Department of Cardiology in Linköping.
    Nordestgaard, Borge G.
    University of Copenhagen, Denmark.
    ODonoghue, John M.
    Global eHealth Unit, School of Public Health, Imperial College London, London, UK.
    Sahebkar, Amirhossein
    Biotechnology Research Center, Mashhad University of Medical Sciences, Mashhad, Iran.
    Schunkert, Heribert
    Deutsches Herzzentrum Munchen, Klinikan der TU Munchen, Munich Heart Alliance, Germany.
    Shehab, Abdulla
    CMHS, UAE University, AlAin, United Arab Emirates.
    Stoll, Mario
    Cardiovascular Genetic Laboratory, Cardiovascular Health Commission, Montevideo, Uruguay.
    Su, Ta-Chen
    Department of Internal Medicine and Cardiovascular Centre, National Taiwan University Hospital, Taipei, Taiwan.
    Susekov, Andrey
    Laboratory of Clinical Lipidology, Cardiology Research Complex, Moscow, Russia.
    Widen, Elisabeth
    Institute for Molecular Medicine Finland FIMM, University of Helsinki, Helsinki, Finland.
    Catapano, Alberico L.
    University of Milan and Multimedica IRCCS Milan, Italy.
    Ray, Kausik K.
    University of London Imperial Coll Science Technology and Med, England.
    Familial hypercholesterolaemia: A global call to arms2015In: Atherosclerosis, ISSN 0021-9150, E-ISSN 1879-1484, Vol. 243, no 1, p. 257-259Article in journal (Refereed)
    Abstract [en]

    n/a

  • 23.
    Vorkapic, Emina
    et al.
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Medicine and Health Sciences.
    Dugic, Elma
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Medicine and Health Sciences.
    Vikingsson, Svante
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Medicine and Health Sciences.
    Roy, Joy
    Vascular Surgery, Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden.
    Mäyränpää, Mikko I.
    Department of Pathology, University of Helsinki, Helsinki, Finland / HUSLAB, Division of Pathology, Meilahti Laboratories of Pathology, Helsinki University Central Hospital, Helsinki, Finland.
    Eriksson, Per
    Karolinska University Hospital, Karolinska Institutet, Stockholm, Sweden.
    Wågsäter, Dick
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Medicine and Health Sciences.
    Imatinib treatment attenuates growth and inflammation of angiotensin II induced abdominal aortic aneurysm2016In: Atherosclerosis, ISSN 0021-9150, E-ISSN 1879-1484, Vol. 249, p. 101-109Article in journal (Refereed)
    Abstract [en]

    AbstractBackground Abdominal aortic aneurysm (AAA) is characterized by vascular remodeling with increased infiltration of inflammatory cells and apoptosis/modulation of vascular smooth muscle cells (SMCs). Imatinib is a selective inhibitor of several tyrosine kinases, including PDGF receptors, Abl, and c-kit. The objective of this study was to characterize the potential protective role of imatinib on AAA development and the molecular mechanisms involved. Methods Male ApoE−/− mice were infused with angiotensin (Ang) II (1000 ng/kg/min) for 4 weeks to induce AAA or saline as controls. Daily treatment with 10 mg/kg imatinib, or tap water as control, was provided via gavage for 4 weeks. Results Treatment with imatinib was found to decrease the aortic diameter and vessel wall thickness, mediated by multiple effects. Imatinib treatment in AngII infused mice resulted in a reduced cellular infiltration of CD3ε positive T lymphocytes by 86% and reduced gene expression of mast cell chymase by 50% compared with AngII infused mice lacking imatinib. Gene expression analysis of SMC marker SM22α demonstrated an increase by 48% together with a more intact medial layer after treatment with imatinib as evaluated with SM22α immunostaining. Conclusion Present findings highlight the importance of tyrosine kinase pathways in the development of AAA. Our results show, that imatinib treatment inhibits essential mast cell, T lymphocyte and SMC mediated processes in experimental AAA. Thus, our results support the idea that tyrosine kinase inhibitors may be useful in the treatment of pathological vascular inflammation and remodeling in conditions like AAA.

  • 24.
    Vorkapic, Emina
    et al.
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Medicine and Health Sciences. Karolinska Institute, Sweden.
    Lundberg, Anna M.
    Karolinska University Hospital Solna, Sweden.
    Mayranpaa, Mikko I.
    University of Helsinki, Finland; University of Helsinki, Finland.
    Eriksson, Per
    Karolinska Institute, Sweden.
    Wågsäter, Dick
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Medicine and Health Sciences. Karolinska Institute, Sweden.
    TRIF adaptor signaling is important in abdominal aortic aneurysm formation2015In: Atherosclerosis, ISSN 0021-9150, E-ISSN 1879-1484, Vol. 241, no 2, p. 561-568Article in journal (Refereed)
    Abstract [en]

    Objective: Abdominal aortic aneurysm (AAA) is characterized by inflammation, loss of smooth muscle cells (SMCs), and degradation of the extracellular matrix in the vessel wall. Innate immune receptors such as Toll-like receptors (TLRs) were recently shown to regulate immunological processes leading to the formation and progression of atherosclerotic plaques as well as to other cardiovascular pathologies. Our aim was to investigate whether blockage of TLR signaling, under the control of TIR domain-containing adaptor protein including IFN-beta (TRIF), could inhibit the inflammatory response and AAA development in mice. Results: In human AAA, an increased TLR3 and TLR4 expression in association with macrophages and T lymphocytes was demonstrated with immunohistochemical analysis. Angiotensin (Ang) II-induced aneurysm formation was significantly reduced by 30% in ApoE(-/-)Trif(-/-) mice compared to ApoE(-/-) mice. Morphologically, AngII-infused ApoE(-/-)Trif(-/-) mice had a more intact cellular and extracellular matrix while ApoE(-/-) mice infused with AngII displayed an increased medial thickness associated with aortic dissection, thrombus formation, and a more disorganized vessel wall. Gene expression analysis of the abdominal aorta revealed a profound decrease of the inflammatory genes CD68 (P less than 0.05), CD11b (P less than 0.05), and TNF-alpha (P less than 0.05) and the protease gene MMP-12 (P less than 0.01) in ApoE(-/-)Trif(-/-) mice compared to ApoE(-/-) mice infused with AngII. Conclusion: Our results suggest that signaling through TRIF is important for the inflammatory response of AngII-induced AAA and that blockage of the TRIF pathway reduces vascular inflammation and protects against AAA formation. (C) 2015 The Authors. Published by Elsevier Ireland Ltd.

  • 25.
    Wagsaeter, Dick
    et al.
    Karolinska Institute.
    Zhu, Chaoyong
    Karolinska Institute.
    Björck, Hanna
    Linköping University, Department of Medicine and Health Sciences, Physiology . Linköping University, Faculty of Health Sciences.
    Eriksson, Per
    Karolinska Institute.
    Effects of PDGF-C and PDGF-D on monocyte migration and MMP-2 and MMP-9 expression2009In: Atherosclerosis, ISSN 0021-9150, E-ISSN 1879-1484, Vol. 202, no 2, p. 415-423Article in journal (Refereed)
    Abstract [en]

    Background and nuns: Atherosclerosis is a chronic inflammatory process involving the activity of several cytokines and growth factors. Platelet-derived growth factor-A (PDGF-A) and PDGF-B are important mitogens and chemoattractants for monocytcs as well as smooth muscle cells. We sought to identify the role of PDGF-C and PDGF-D, two new members of the PDGF family, in monocyte migration and differentiation. We also assessed their effects in regulating matrix metalloproteinase-2 (MMP-2) and MMP-9. which are important for cell migration.

    Methods and results: PDGF-C and PDGF-D were expressed in macrophages, smooth muscle cells, and endothelial cells in human atherosclerotic plaques, as shown by immunohistochemical analysis. PDGF-C and PDGF-I) mRNA and protein expression was induced after differentiation of THP-1 monocytes to macrophages, and both PDGF-C and PDGF-D induced MMP-9 mRNA expression in a concentration-dependent manner. Treatment of cells with PDGF-C or PDGF-D enhanced the secretion of MMP-2 and MMP-9 in a cell-dependent manner. In a migration assay using a Boyden chamber with 8 mu m pore size, PDGF-C and PDGF-D attracted THP-1 monocytes in a concentration-dependent manner.

    Conclusions: Our data suggest that PDGF-C and PDGF-D, like PDGF-A and PDGF-B, play important roles in atherosclerosis by stimulating MMP activity and influencing monocyte migration.

  • 26.
    Wanhainen, Anders
    et al.
    Uppsala University, Uppsala, Sweden .
    Mani, Kevin
    Uppsala University, Uppsala, Sweden .
    Vorkapic, Emina
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Medicine and Health Sciences.
    De Basso, Rachel
    Jönköping University, Jönköping, Sweden.
    Björck, Martin
    Uppsala University, Uppsala, Sweden .
    Länne, Toste
    Linköping University, Department of Medical and Health Sciences, Division of Cardiovascular Medicine. Region Östergötland, Heart and Medicine Center, Department of Thoracic and Vascular Surgery. Linköping University, Faculty of Medicine and Health Sciences.
    Wågsäter, Dick
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Medicine and Health Sciences.
    Screening of circulating microRNA biomarkers for prevalence of abdominal aortic aneurysm and aneurysm growth.2017In: Atherosclerosis, ISSN 0021-9150, E-ISSN 1879-1484, Vol. 256, p. 82-88Article in journal (Refereed)
    Abstract [en]

    BACKGROUND AND AIMS: MicroRNA (miR) are important regulators of gene expression and biological processes and have recently been suggested as possible biomarkers for abdominal aortic aneurysm (AAA) disease. The aim of the present study was to assess the role of miR as biomarkers for initiation and progression of AAA disease, through evaluation of a wide range of miRs in a large population-based cohort, with AAA patients with linked clinical data regarding risk factors, AAA size and growth, as well as controls.

    METHODS: The expression of the 172 most commonly expressed miRs in plasma was analyzed by real-time PCR in samples from 169 screening-detected AAA patients and 48 age-matched controls.

    RESULTS: For 103 miRs, there was a significant difference in expression between AAA and controls. Of these, 20 miRs were differently expressed between fast and slow growing aneurysms. These miRs target genes known to be involved in AAA disease as well as novel genes and pathways. By combining the top altered miRs together with clinical variables, strong predictive values, determining growth of AAA, were obtained (area under curve = 0.86, p < 0.001).

    CONCLUSIONS: This large cohort study identified several novel miRs with altered expression in AAA patients when compared to controls. Assessment of miR expression may offer an opportunity to predict disease progression and aneurysm growth.

  • 27.
    Wågsäter, Dick
    et al.
    Karolinska Institute, Stockholm, Sweden.
    Björk, Hanna
    Karolinska Institute, Stockholm, Sweden.
    Zhu, Chaoyong
    Karolinska Institute, Stockholm, Sweden.
    Björkegren, Johan
    Karolinska Institute, Stockholm, Sweden.
    Valen, Guro
    University of Oslo, Norway .
    Hamsten, Anders
    Karolinska Institute, Stockholm, Sweden.
    Eriksson, Per
    Karolinska Institute, Stockholm, Sweden.
    ADAMTS-4 and-8 are inflammatory regulated enzymes expressed in macrophage-rich areas of human atherosclerotic plaques2008In: Atherosclerosis, ISSN 0021-9150, E-ISSN 1879-1484, Vol. 196, no 2, p. 514-522Article in journal (Refereed)
    Abstract [en]

    OBJECTIVES:

    Remodeling of extracellular matrix (ECM) plays an important role in inflammatory disorders such as atherosclerosis. ADAMTS (a disintegrin and metalloproteinase with thrombospondin motifs) is a recently described family of proteinases that is able to degrade the ECM proteins aggrecan and versican expressed in blood vessels. The purpose of the present study was to analyze the expression and regulation of several ADAMTSs before and after macrophage differentiation and after stimulation with IFN-gamma, IL-1beta and TNF-alpha. ADAMTS expression was also examined during atherosclerosis development in mice and in human atherosclerotic plaques.

    METHODS AND RESULTS:

    Real time RTPCR showed that, of the nine different ADAMTS members examined, only ADAMTS-4 and -8 were induced during monocyte to macrophage differentiation, which was also seen at protein level. Macrophage expression of ADAMTS-4, -7, -8 and -9 mRNA were enhanced upon stimulation with IFN-gamma or TNF-alpha. Furthermore, immunohistochemical analyses revealed that ADAMTS-4 and -8 were expressed in macrophage rich areas of human atherosclerotic carotid plaques and coronary unstable plaques. In addition, ADAMTS-4 expression was upregulated during the development of atherosclerosis in LDLR(-/-)ApoB(100/100) mice. Whereas ADAMTS-4 expression was low in non-atherosclerotic aortas, it was significantly higher in aortas from 30-40-week old atherosclerotic animals.

    CONCLUSION:

    The present study suggests that ADAMTS-4 and -8 are inflammatory regulated enzymes expressed in macrophage-rich areas of atherosclerotic plaques. This is the first study associating ADAMTS-4 and -8 expression with atherosclerosis. However, further experiments are required to understand the physiological and pathological functions of ADAMTS in the vascular wall, and tools to measure ADAMTS activity need to be developed.

  • 28.
    Yuan, XiMing
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Experimental Pathology. Linköping University, Faculty of Health Sciences.
    Li, Wei
    Linköping University, Department of Medicine and Health Sciences. Linköping University, Faculty of Health Sciences.
    Olsson, Anders
    Linköping University, Department of Medicine and Health Sciences, Internal Medicine. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Heart and Medicine Centre, Department of Endocrinology and Gastroenterology UHL.
    Brunk, Ulf
    Linköping University, Department of Medicine and Health Sciences, Pharmacology. Linköping University, Faculty of Health Sciences.
    The toxicity to macrophages of oxidized low-density lipoprotein is mediated through lysosomal damage1997In: Atherosclerosis, ISSN 0021-9150, E-ISSN 1879-1484, Vol. 133, no 2, p. 153-61Article in journal (Refereed)
    Abstract [en]

    Oxidized low-density lipoprotein (ox-LDL) has been shown to degrade poorly within the secondary lysosomes of macrophages but its possible effect on lysosomal integrity has received less attention. The effect of ultraviolet-C oxidized LDL (UVox-LDL) on cellular viability, and lysosomal membrane stability, was examined on cultured murine J-774 cells and human monocyte-derived macrophages (HMDMs). The acridine orange (AO) relocalization test was applied to study the lysosomal integrity of living cells. UVox-LDL dramatically reduced J-774 cell proliferation at a concentration of 25 microg/ml. Incubation with 5 microM copper alone, normally used to induce LDL oxidation, was also toxic. In contrast to the effects of ox-LDL, in concentrations up to 75 microg/ml, native LDL (nLDL) rather stimulated J-774 cell replication. Incubation with UVox-LDL (25-75 microg/ml) also altered cellular AO uptake, depending on time and dose: its lysosomal accumulation decreased and its cytosolic accumulation increased. This shift indicates damaged lysosomal membranes with decreased intralysosomal, and increased cytosolic, H+ concentration. Many J-774 cells exposed to UVox-LDL initially transformed into foam cells and then assumed an apoptotic-type morphology with TUNEL-positive nuclei. We conclude that ox-LDL is cytotoxic to macrophages due to oxidative damage of lysosomal membranes, with ensuing destabilization and leakage to the cytosol of lysosomal contents, such as hydrolytic enzymes, causing degeneration of apoptotic type.

  • 29.
    Yuan, XiMing
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Experimental Pathology. Linköping University, Faculty of Health Sciences.
    Olsson, Anders
    Linköping University, Department of Medicine and Health Sciences, Internal Medicine. Linköping University, Faculty of Health Sciences.
    Brunk, Ulf
    Linköping University, Department of Medicine and Health Sciences, Pharmacology. Linköping University, Faculty of Health Sciences.
    Iron in human atheroma and LDL oxidation by macrophages following erythrophagocytosis1996In: Atherosclerosis, ISSN 0021-9150, E-ISSN 1879-1484, Vol. 124, no 1, p. 61-73Article in journal (Refereed)
    Abstract [en]

    The oxidative modification of low density lipoprotein (LDL) has been implicated as an early step in the formation of atheromatous lesions. In vitro studies suggest it to be accelerated, or even initiated, by transition metals such as iron or copper in combination with a reducing agent. Even if such metals have been demonstrated in atheroma gruels, their origin and precise localisation within human atheroma are presently unknown. In the initial part of this study we applied Pearl's method, energy dispersive X-ray microanalysis, and a modified Timm sulphide silver method (SSM) to demonstrate the occurrence of iron in early atherosclerotic lesions from a number of consecutive autopsy cases with evident, general atheromatosis. With the very sensitive SSM, but not with the other techniques, we found foam cells to contain heavy metals with a mainly lysosomal localization. On the basis of the hypothesis that such a lysosomal accumulation of iron might be due to erythrophagocytosis by migrating tissue-bound macrophages that later develop into foam cells, we designed an in vitro model system where human monocyte-derived macrophages were exposed to artificially aged, UV-exposed erythrocytes. The macrophages were then exposed to LDL in serum-and iron-free RPMI medium, occasionally in the presence of the potent iron-chelator desferrioxamine. The capacity of macrophages to oxidise LDL was much enhanced following erythrophagocytosis, and the process was shown to involve secretion of iron. Consequently, LDL oxidation was greatly inhibited by desferrioxamine. We conclude that iron may be exocytosed by macrophages that previously had their lysosomal apparatus enriched with iron, e.g. due to erythrophagocytosis. Oxidation of LDL may result in ensuing foam cell-formation secondary to scavenger-receptor mediated endocytosis by macrophages.

  • 30.
    Yuan, Xi-Ming
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Experimental Pathology. Linköping University, Faculty of Health Sciences.
    Osman, Ehab
    Linköping University, Department of Clinical and Experimental Medicine, Experimental Pathology. Linköping University, Faculty of Health Sciences.
    Miah, Sayem
    Linköping University, Department of Medical and Health Sciences, Pharmacology. Linköping University, Faculty of Health Sciences.
    Zadeh, Shahram Nour Mohammad
    Linköping University, Department of Clinical and Experimental Medicine, Experimental Pathology. Linköping University, Faculty of Health Sciences.
    Xu, Lihua
    Linköping University, Department of Clinical and Experimental Medicine, Experimental Pathology. Linköping University, Faculty of Health Sciences.
    Forssell, Claes
    Linköping University, Department of Medical and Health Sciences, Vascular surgery. Linköping University, Faculty of Health Sciences.
    Li, Wei
    Linköping University, Department of Medical and Health Sciences, Pharmacology. Linköping University, Faculty of Health Sciences.
    p53 expression in human carotid atheroma is significantly related to plaque instability and clinical manifestations2010In: Atherosclerosis, ISSN 0021-9150, E-ISSN 1879-1484, Vol. 210, no 2, p. 392-399Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE: The expression of p53 has been associated with DNA damage, cell senescence, proliferation and apoptosis in human atherosclerotic plaques. However, it is largely unknown whether p53 expression is related to the stability and clinical manifestations of atherosclerotic plaques in humans. In the present study, we examined whether p53 expression is related to clinical symptoms and plaque integrity in patients with carotid atherosclerosis (n=62). We also investigated p53 expression and its relation to apoptosis and apoptosis-related cathepsin L and ferritin in the carotid lesions. METHODS AND RESULTS: We found that smooth muscle cells often had nuclear p53 in the shoulder region of carotid lesions while CD68-positive macrophages, which had both nuclear and cytoplasmic p53, frequently appeared in the surrounding areas of necrotic cores or plaque cap regions. Quantitative image analysis of immunohistochemistry showed that p53 expression was significantly increased in plaques with necrotic core formation or cap rupture and lesions from patients with transient ischemic attacks (TIAs). The levels of p53 expression was significantly increased in more severe stenosed lesions but decreased with prolonged time between symptom onset and carotid endarterectomy. Furthermore, p53 expression was significantly correlated with the expression of ferritin, lysosomal cathepsin L, and apoptosis. CONCLUSION: The increased p53 expression, particularly macrophage p53 levels, is associated with the enlargement of necrotic cores, plaque rupture and clinical manifestations of carotid plaques. Concomitant increases of lysosomal cathepsin, ferritin, and p53 levels may promote the apoptosis and atheroma progression in patients with carotid atherosclerosis.

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