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  • 1.
    Ali, Zaheer
    et al.
    Linköping University, Department of Medical and Health Sciences, Division of Cardiovascular Medicine. Linköping University, Faculty of Medicine and Health Sciences.
    Mukwaya, Anthonny
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences.
    Biesemeier, Antje
    Univ Tubingen, Germany.
    Ntzouni, Maria
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences.
    Ramskold, Daniel
    Karolinska Inst, Sweden.
    Giatrellis, Sarantis
    Karolinska Inst, Sweden.
    Mammadzada, Parviz
    Karolinska Inst, Sweden.
    Cao, Renhai
    Karolinska Inst, Sweden.
    Lennikov, Anton
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences. Univ Missouri, MO 65211 USA.
    Marass, Michele
    Max Planck Inst Lung and Heart Res, Germany.
    Gerri, Claudia
    Max Planck Inst Lung and Heart Res, Germany.
    Hildesjö, Camilla
    Linköping University, Department of Clinical and Experimental Medicine, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Clinical pathology.
    Taylor, Michael
    Univ Wisconsin, WI 53706 USA.
    Deng, Qiaolin
    Karolinska Inst, Sweden.
    Peebo, Beatrice
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Anaesthetics, Operations and Specialty Surgery Center, Department of Ophthalmology in Linköping. Bayer AB, Sweden.
    del Peso, Luis
    Universidad Autónoma de Madrid, Spain; Instituto de Investigaciones Biomédicas Alberto Sols, CSIC-UAM Madrid, Spain.
    Kvanta, Anders
    Karolinska Inst, Sweden.
    Sandberg, Rickard
    Karolinska Inst, Sweden.
    Schraermeyer, Ulrich
    Univ Tubingen, Germany.
    Andre, Helder
    Karolinska Inst, Sweden.
    Steffensen, John F.
    Univ Copenhagen, Denmark.
    Lagali, Neil
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Anaesthetics, Operations and Specialty Surgery Center, Department of Ophthalmology in Linköping.
    Cao, Yihai
    Karolinska Inst, Sweden.
    Kele, Julianna
    Karolinska Inst, Sweden.
    Jensen, Lasse
    Linköping University, Department of Medical and Health Sciences, Division of Cardiovascular Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Department of Clinical Pharmacology. Univ Autonoma Madrid, Spain; UAM, Spain.
    Intussusceptive Vascular Remodeling Precedes Pathological Neovascularization2019In: Arteriosclerosis, Thrombosis and Vascular Biology, ISSN 1079-5642, E-ISSN 1524-4636, Vol. 39, no 7, p. 1402-1418Article in journal (Refereed)
    Abstract [en]

    Objective—

    Pathological neovascularization is crucial for progression and morbidity of serious diseases such as cancer, diabetic retinopathy, and age-related macular degeneration. While mechanisms of ongoing pathological neovascularization have been extensively studied, the initiating pathological vascular remodeling (PVR) events, which precede neovascularization remains poorly understood. Here, we identify novel molecular and cellular mechanisms of preneovascular PVR, by using the adult choriocapillaris as a model.

    Approach and Results—

    Using hypoxia or forced overexpression of VEGF (vascular endothelial growth factor) in the subretinal space to induce PVR in zebrafish and rats respectively, and by analyzing choriocapillaris membranes adjacent to choroidal neovascular lesions from age-related macular degeneration patients, we show that the choriocapillaris undergo robust induction of vascular intussusception and permeability at preneovascular stages of PVR. This PVR response included endothelial cell proliferation, formation of endothelial luminal processes, extensive vesiculation and thickening of the endothelium, degradation of collagen fibers, and splitting of existing extravascular columns. RNA-sequencing established a role for endothelial tight junction disruption, cytoskeletal remodeling, vesicle- and cilium biogenesis in this process. Mechanistically, using genetic gain- and loss-of-function zebrafish models and analysis of primary human choriocapillaris endothelial cells, we determined that HIF (hypoxia-induced factor)-1α-VEGF-A-VEGFR2 signaling was important for hypoxia-induced PVR.

    Conclusions—

    Our findings reveal that PVR involving intussusception and splitting of extravascular columns, endothelial proliferation, vesiculation, fenestration, and thickening is induced before neovascularization, suggesting that identifying and targeting these processes may prevent development of advanced neovascular disease in the future.

    Visual Overview—

    An online visual overview is available for this article.

  • 2.
    Buehler, Alexandra
    et al.
    CARIM, University of Maastricht, The Netherlands.
    van Zandvoort, Marc
    CARIM, University of Maastricht, The Netherlands.
    Stelt, Bram
    CARIM, University of Maastricht, The Netherlands.
    Hackeng, Tilman
    CARIM, University of Maastricht, The Netherlands.
    Schrans-Stassen, Bianca
    CARIM, University of Maastricht, The Netherlands.
    Bennaghmouch, Abdelkader
    CARIM, University of Maastricht, The Netherlands.
    Hofstra, Leo
    CARIM, University of Maastricht, The Netherlands.
    Cleutjens, Jack
    CARIM, University of Maastricht, The Netherlands.
    Duijvestijn, Adriaan
    CARIM, University of Maastricht, The Netherlands.
    Smeets, Mirjam
    University Hospital Utrecht, The Netherlands.
    de Kleijn, Dominique
    University Hospital Utrecht, The Netherlands.
    Post, Mark
    University Hospital Utrecht, The Netherlands.
    de Muinck, Ebo D.
    Dartmouth Medical School, Hanover, NH, USA.
    cNGR: A novel homing sequence for CD13/APN targeted molecular imaging of murine cardiac angiogenesis in vivo2006In: Arteriosclerosis, Thrombosis and Vascular Biology, ISSN 1079-5642, E-ISSN 1524-4636, Vol. 26, no 12, p. 2681-2687Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE:

    Previously, the peptide sequence cNGR has been shown to home specifically to CD13/APN (aminopeptidase N) on tumor endothelium. Here, we investigated the feasibility of selective imaging of cardiac angiogenesis using the cNGR-CD13/APN system.

    METHODS AND RESULTS:

    CD13/APN induction and cNGR homing were studied in the murine myocardial infarction (MI) model. By real-time polymerase chain reaction (PCR) at 7 days after MI, CD13/APN expression was 10- to 20-fold higher in the angiogenic infarct border zone and the MI area than in non-MI areas. In vivo fluorescence microscopy confirmed specific homing of fluorophore-tagged cNGR to the border zone and MI territory at 4 and 7 days after MI with a local advantage of 2.3, but not at 1 or 14 days after MI. Tissue residence half-life was 9.1+/-0.3 hours, whereas the half-life in plasma was 15.4+/-3.4 minutes. Pulse chase experiments confirmed reversible binding of cNGR in the infarct area. Fluorescent labeled cNGR conjugates or antibodies were injected in vivo, and their distribution was studied ex vivo by 2-photon laser scanning microscopy (TPLSM). cNGR co-localized exclusively with CD13/APN and the endothelial marker CD31 on vessels.

    CONCLUSIONS:

    In cardiac angiogenesis endothelial CD13/APN is upregulated. It can be targeted specifically with cNGR conjugates. In the heart cNGR binds its endothelial target only in angiogenic areas.

  • 3.
    Dudman, N. P. B.
    et al.
    Department of Medicine, University of New South Wales, Prince Henry Hospital, Uttle Bay, UK.
    Wilcken, D. E.
    Department of Medicine, University of New South Wales, Prince Henry Hospital, Uttle Bay, UK.
    Wang, J.
    Department of Medicine, University of New South Wales, Prince Henry Hospital, Uttle Bay, UK.
    Lynch, J. F.
    Department of Medicine, University of New South Wales, Prince Henry Hospital, Uttle Bay, UK.
    Macey, D.
    Department of Medicine, University of New South Wales, Prince Henry Hospital, Uttle Bay, UK.
    Lundberg, Peter
    Linköping University, Department of Medical and Health Sciences, Division of Radiological Sciences. Linköping University, Faculty of Health Sciences. Linköping University, Center for Medical Image Science and Visualization (CMIV). Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Radiation Physics. Department of Biochemistry, University of Sydney, Sydney (P.L.), Australia.
    Disordered methionine/homocysteine metabolism in premature vascular disease. Its occurrence, cofactor therapy, and enzymology1993In: Arteriosclerosis, Thrombosis and Vascular Biology, ISSN 1079-5642, E-ISSN 1524-4636, Vol. 13, no 9, p. 1253-1260Article in journal (Refereed)
    Abstract [en]

    Mild homocysteinemia occurs surprisingly often in patients with premature vascular disease. We studied the possible enzymatic sources of this mild hyperhomocysteinemia and the control of homocysteine levels in plasma by treatment of patients with the cofactors and cosubstrates of homocysteine catabolism. We assessed homocysteine metabolism in 131 patients who had premature disease in their coronary, peripheral, or cerebrovascular circulation by using a standard oral methionine-load test. Impaired homocysteine metabolism occurred in 28 patients. We assayed levels of the primary enzymes of homocysteine catabolism in cultured skin fibroblast extracts from 15 of these 28 patients. The patients' cystathionine beta-synthase levels (3.68 +/- 2.52 nmol/h per milligram of cell protein, mean +/- SD) were markedly depressed compared with those from 31 healthy adult control subjects (7.61 +/- 4.49, P < .001). The patients' levels of 5-methyltetrahydrofolate: homocysteine methyltransferase were normal. While betaine: homocysteine methyltransferase was not expressed in skin fibroblasts, 24-hour urinary betaine and N,N-dimethylglycine measurements were consistent with normal or enhanced remethylation of homocysteine by betaine: homocysteine methyltransferase in the 13 patients tested. When treated daily with choline and betaine, pyridoxine, or folic acid, there was a normalization of the postmethionine plasma homocysteine level in 16 of 19 patients. Our results indicate that mild homocysteinemia in premature vascular disease may be caused by either a folate deficiency or deficiencies in cystathionine beta-synthase activity. It does not necessarily involve deficiencies of either 5-methyltetrahydrofolate:homocysteine methyltransferase or betaine:homocysteine methyltransferase. Effective treatment regimens are also defined.

  • 4.
    Jensen, Lasse
    et al.
    Linköping University, Department of Medical and Health Sciences, Division of Cardiovascular Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Department of Clinical Pharmacology.
    Hot, Belma
    Karolinska Inst, Sweden; Ludwig Inst Canc Res Ltd, Sweden.
    Ramskold, Daniel
    Karolinska Inst, Sweden; Ludwig Inst Canc Res Ltd, Sweden.
    Germano, Raoul F. V.
    Univ Libre Bruxelles, Belgium.
    Yokota, Chika
    Ludwig Inst Canc Res Ltd, Sweden; Stockholm Univ, Sweden.
    Giatrellis, Sarantis
    Karolinska Inst, Sweden.
    Lauschke, Volker M.
    Karolinska Inst, Sweden.
    Hubmacher, Dirk
    Icahn Sch Med Mt Sinai, NY 10029 USA.
    Li, Minerva X.
    Ludwig Inst Canc Res Ltd, Sweden; Lund Univ, Sweden.
    Hupe, Mike
    Ludwig Inst Canc Res Ltd, Sweden; Univ Wurzburg, Germany.
    Arnold, Thomas D.
    Univ Calif San Francisco, CA 94143 USA.
    Sandberg, Rickard
    Karolinska Inst, Sweden; Ludwig Inst Canc Res Ltd, Sweden.
    Frisen, Jonas
    Karolinska Inst, Sweden.
    Trusohamn, Marta
    Karolinska Inst, Sweden.
    Martowicz, Agnieszka
    Karolinska Inst, Sweden.
    Wisniewska-Kruk, Joanna
    Karolinska Inst, Sweden.
    Nyqvist, Daniel
    Karolinska Inst, Sweden.
    Adams, Ralf H.
    Univ Munster, Germany.
    Apte, Suneel S.
    Cleveland Clin Fdn, OH 44195 USA.
    Vanhollebeke, Benoit
    Univ Libre Bruxelles, Belgium; Walloon Excellence Life Sci and Biotechnol WELBIO, Belgium.
    Stenman, Jan M.
    Ludwig Inst Canc Res Ltd, Sweden.
    Kele, Julianna
    Karolinska Inst, Sweden; Ludwig Inst Canc Res Ltd, Sweden.
    Disruption of the Extracellular Matrix Progressively Impairs Central Nervous System Vascular Maturation Downstream of beta-Catenin Signaling2019In: Arteriosclerosis, Thrombosis and Vascular Biology, ISSN 1079-5642, E-ISSN 1524-4636, Vol. 39, no 7, p. 1432-1447Article in journal (Refereed)
    Abstract [en]

    Objective- The Wnt/beta-catenin pathway orchestrates development of the blood-brain barrier, but the downstream mechanisms involved at different developmental windows and in different central nervous system (CNS) tissues have remained elusive. Approach and Results- Here, we create a new mouse model allowing spatiotemporal investigations of Wnt/beta-catenin signaling by induced overexpression of Axin1, an inhibitor of beta-catenin signaling, specifically in endothelial cells (Axin1(iEC)-(OE)). AOE (Axin1 overexpression) in Axin1(iEC)-(OE) mice at stages following the initial vascular invasion of the CNS did not impair angiogenesis but led to premature vascular regression followed by progressive dilation and inhibition of vascular maturation resulting in forebrain-specific hemorrhage 4 days post-AOE. Analysis of the temporal Wnt/beta-catenin driven CNS vascular development in zebrafish also suggested that Axin1(iEC)-(OE) led to CNS vascular regression and impaired maturation but not inhibition of ongoing angiogenesis within the CNS. Transcriptomic profiling of isolated, beta-catenin signaling-deficient endothelial cells during early blood-brain barrier-development (E11.5) revealed ECM (extracellular matrix) proteins as one of the most severely deregulated clusters. Among the 20 genes constituting the forebrain endothelial cell-specific response signature, 8 (Adamtsl2, Apod, Ctsw, Htra3, Pglyrp1, Spock2, Ttyh2, and Wfdc1) encoded bona fide ECM proteins. This specific beta-catenin-responsive ECM signature was also repressed in Axin1(iEC)-(OE) and endothelial cell-specific beta-catenin-knockout mice (Ctnnb1-KOiEC) during initial blood-brain barrier maturation (E14.5), consistent with an important role of Wnt/beta-catenin signaling in orchestrating the development of the forebrain vascular ECM. Conclusions- These results suggest a novel mechanism of establishing a CNS endothelium-specific ECM signature downstream of Wnt-beta-catenin that impact spatiotemporally on blood-brain barrier differentiation during forebrain vessel development.

  • 5.
    Kinlay, S.
    et al.
    Cardiovascular Division, Veterans Affairs Boston Healthcare System, West Roxbury, MA, United States, Cardiovascular Division, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, United States, Brigham and Women's Hospital, 75 Francis Street, Boston, MA 02115, United States.
    Schwartz, G.G.
    Cardiology Division, Veterans Affairs Medical Center, University of Colorado Health Sciences Center, Denver, CO, United States.
    Olsson, Anders G.
    Linköping University, Department of Medical and Health Sciences, Internal Medicine. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Heart and Medicine Centre, Department of Endocrinology and Gastroenterology UHL.
    Rifai, N.
    Children's Hospital Boston, Harvard Medical School, Boston, MA, United States.
    Szarek, M.
    Pfizer Pharmaceuticals Group, New York, NY, United States.
    Waters, D.D.
    Cardiology Division, San Francisco General Hospital, University of California, San Francisco, CA, United States.
    Libby, P.
    Cardiovascular Division, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, United States.
    Ganz, P.
    Cardiovascular Division, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, United States.
    Inflammation, statin therapy, and risk of stroke after an acute coronary syndrome in the MIRACL study2008In: Arteriosclerosis, Thrombosis and Vascular Biology, ISSN 1079-5642, E-ISSN 1524-4636, Vol. 28, no 1, p. 142-147Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE - Patients with acute coronary syndromes have an increased risk of stroke. We measured markers of inflammation in the MIRACL study, a randomized trial of atorvastatin versus placebo in acute coronary syndromes, to assess the relationship of inflammation to stroke. METHODS AND RESULTS - Baseline C-reactive protein (CRP), serum amyloid A (SAA), and interleukin-6 (IL-6) were collected in 2926 (95%) subjects. Baseline markers were related to stroke risk over the 16 weeks of the study. Subjects who subsequently experienced a stroke had higher CRP (27.5 versus 10.2 mg/L, P=0.0032), SAA (30.5 versus 16.0 mg/L, P=0.031), IL-6 (11 231 versus 6841 pg/L, P=0.004), and troponin (6.03 versus 3.19 ng/mL P=0.0032). The risk of stroke was related to greater CRP, SAA, and IL-6 in the placebo group only. Similarly, there was a graded increase in risk of stroke across quartiles of inflammatory markers in the placebo patients only. CONCLUSIONS - In acute coronary syndromes, the early risk of stroke relates to both heightened inflammation and size of myocardial necrosis. Treatment with atorvastatin abrogated the risk associated with elevated markers of inflammation in this study, a finding that provides a novel rationale for the use of statins in acute coronary syndromes. © 2008 American Heart Association, Inc.

  • 6.
    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.

     

  • 7.
    Li, Wei
    et al.
    Linköping University, Department of Neuroscience and Locomotion, Pathology. Linköping University, Faculty of Health Sciences.
    Dalen, Helge
    Department of Pathology, Gade Institute, University of Bergen, Bergen, Norway.
    Eaton, John Wallace
    The James Graham Brown Cancer Center, University of Louisville, Louisville, Ky.
    Yuan, Xi Ming
    Linköping University, Department of Neuroscience and Locomotion, Pathology. Linköping University, Faculty of Health Sciences.
    Apoptotic Death of Inflammatory Cells in Human Atheroma2001In: Arteriosclerosis, Thrombosis and Vascular Biology, ISSN 1079-5642, E-ISSN 1524-4636, Vol. 21, no 7, p. 1124-1130Article in journal (Refereed)
    Abstract [en]

    Although the accumulation of cholesterol and other lipidic material is unquestionably important in atherogenesis, the reasons why this material progressively accumulates, rather than being effectively cleared by phagocytic cells such as macrophages, are not completely understood. We hypothesize that atheromatous lesions may represent "death zones" that contain toxic materials such as oxysterols and in which monocytes/macrophages become dysfunctional and apoptotic. Indeed, cathepsins B and L, normally confined to the lysosomal compartment, are present in the cytoplasm and nuclei of apoptotic (caspase-3-positive) macrophages within human atheroma. The possible involvement of oxysterols is suggested by experiments in which cultured U937 and THP-1 cells exposed to 7-oxysterols similarly undergo marked lysosomal destabilization, caspase-3 activation, and apoptosis. Like macrophages within atheroma, intralysosomal cathepsins B and L are normally present in the cytoplasm and nuclei of these oxysterol-exposed cells. Lysosomal destabilization, cathepsin release, and apoptosis may be causally related, because inhibitors of cathepsins B and L suppress oxysterol-induced apoptosis. Thus, toxic materials such as 7-oxysterols in atheroma may impair the clearance of cholesterol and other lipidic material by fostering the apoptotic death of phagocytic cells, thereby contributing to further development of atherosclerotic lesions.

  • 8.
    Li, Wei
    et al.
    Linköping University, Department of Neuroscience and Locomotion, Pathology. Linköping University, Department of Medicine and Care, Internal Medicine. Linköping University, Faculty of Health Sciences.
    Yuan, Xi Ming
    Linköping University, Department of Neuroscience and Locomotion, Pathology. Linköping University, Department of Medicine and Care, Internal Medicine. Linköping University, Faculty of Health Sciences.
    Olsson, Anders
    Linköping University, Department of Medical and Health Sciences, Internal Medicine. Linköping University, Faculty of Health Sciences.
    Brunk, Ulf
    Linköping University, Department of Neuroscience and Locomotion, Pathology. Linköping University, Faculty of Health Sciences.
    Uptake of Oxidized LDL by Macrophages Results in Partial Lysosomal Enzyme Inactivation and Relocation1998In: Arteriosclerosis, Thrombosis and Vascular Biology, ISSN 1079-5642, E-ISSN 1524-4636, Vol. 18, no 2, p. 177-84Article in journal (Refereed)
    Abstract [en]

    The cytotoxicity of oxidized LDL (oxLDL) to several types of artery wall cells might contribute to atherosclerosis by causing cell death, presumably by both apoptosis and necrosis. After its uptake into macrophage lysosomes by receptor-mediated endocytosis, oxLDL is poorly degraded, resulting in ceroid-containing foam cells. We studied the influence of oxLDL on lysosomal enzyme activity and, in particular, on lysosomal membrane stability and the modulation of these cellular characteristics by HDL and vitamin E (vit-E). Unexposed cells and cells exposed to acetylated LDL (AcLDL) were used as controls. The lysosomal marker enzymes cathepsin L and N-acetyl-β-glucosaminidase (NAβGase) were biochemically assayed in J-774 cells after fractionation. Lysosomal integrity in living cells was assayed by the acridine orange (AO) relocation test. Cathepsin D was immunocytochemically demonstrated in J-774 cells and human monocyte-derived macrophages. We found that the total activities of NAβGase and cathepsin L were significantly decreased, whereas their relative cytosolic activities were enhanced, after oxLDL exposure. Labilization of the lysosomal membranes was further proven by decreased lysosomal AO uptake and relocation to the cytosol of cathepsin D, as estimated by light and electron microscopic immunocytochemistry. HDL and vit-E diminished the cytotoxicity of oxLDL by decreasing the lysosomal damage. The results indicate that endocytosed oxLDL not only partially inactivates lysosomal enzymes but also destabilizes the acidic vacuolar compartment, causing relocation of lysosomal enzymes to the cytosol. Exposure to AcLDL resulted in its uptake with enlargement of the lysosomal apparatus, but the stability of the lysosomal membranes was not changed.

  • 9.
    Li, Wei
    et al.
    Linköping University, Department of Clinical and Experimental Medicine.
    Yuan, Xi-Ming
    Linköping University, Department of Clinical and Experimental Medicine.
    Olsson, AG
    Brunk, UT
    Uptake of oxidized LDL by macrophages results in partial lysosomal enzyme inactivation and relocation.1998In: Arteriosclerosis, Thrombosis and Vascular Biology, ISSN 1079-5642, E-ISSN 1524-4636, Vol. 18, p. 177-184Article in journal (Other academic)
    Abstract [en]

    he cytotoxicity of oxidized LDL (oxLDL) to several types of artery wall cells might contribute to atherosclerosis by causing cell death, presumably by both apoptosis and necrosis. After its uptake into macrophage lysosomes by receptor-mediated endocytosis, oxLDL is poorly degraded, resulting in ceroid-containing foam cells. We studied the influence ofoxLDL on lysosomal enzyme activity and, in particular, on lysosomal membrane stability and the modulation of these cellular characteristics by HDL and vitamin E (vit-E). Unexposed cells and cells exposed to acetylated LDL (AcLDL) were used as controls. The lysosomal marker enzymes cathepsin L and N-acetyl-beta-glucosaminidase (NAbetaGase) were biochemically assayed in J-774 cells after fractionation. Lysosomal integrity in living cells was assayed by the acridine orange (AO) relocation test. Cathepsin D was immunocytochemically demonstrated in J-774 cells and human monocyte-derived macrophages. We found that the total activities of NAbetaGase and cathepsin L were significantly decreased, whereas their relative cytosolic activities were enhanced, after oxLDL exposure. Labilization of the lysosomal membranes was further proven by decreased lysosomal AO uptake and relocation to the cytosol of cathepsin D, as estimated by light and electron microscopic immunocytochemistry. HDL and vit-E diminished the cytotoxicity of oxLDL by decreasing the lysosomal damage. The results indicate that endocytosed oxLDL not only partially inactivates lysosomal enzymes but also destabilizes the acidic vacuolar compartment, causing relocation of lysosomal enzymes to the cytosol. Exposure to AcLDL resulted in its uptake with enlargement of the lysosomal apparatus, but the stability of the lysosomal membranes was not changed.

  • 10.
    Olofsson, P. S.
    et al.
    Karolinska Institutet, Stockholm, Sweden.
    Jatta, K.
    University of Örebro, Sweden.
    Wågsäter, Dick
    University of Örebro, Sweden.
    Gredmark, S.
    Karolinska Institutet, Stockholm, Sweden.
    Hedin, U.
    Karolinska Institutet, Stockholm, Sweden.
    Paulsson-Berne, G.
    Karolinska Institutet, Stockholm, Sweden.
    Söderberg-Nauclér, C.
    Karolinska Institutet, Stockholm, Sweden.
    Hansson, G. K.
    Karolinska Institutet, Stockholm, Sweden.
    Sirsjö, A.
    University of Örebro, Sweden.
    The antiviral cytomegalovirus inducible gene 5/viperin is expressed in atherosclerosis and regulated by proinflammatory agents2005In: Arteriosclerosis, Thrombosis and Vascular Biology, ISSN 1079-5642, E-ISSN 1524-4636, Vol. 25, no 7, p. E113-E116Article in journal (Refereed)
    Abstract [en]

    Objective-Inflammatory processes play an important role in atherosclerosis, and increasing evidence implies that microbial pathogens and proinflammatory cytokines are involved in the development and activation of atherosclerotic lesions. To find new inflammatory genes, we explored the vascular transcriptional response to an activator of innate immunity bacterial lipopolysaccharides (LPSs). Methods and Results-Gene arrays identified the cytomegalovirus-inducible gene 5 (cig5)/viperin among the genes most potently induced by LPS in human vascular biopsies. Viperin was expressed by endothelial cells in atherosclerotic arteries and significantly elevated in atherosclerotic compared with normal arteries. In culture, cytomegalovirus infection, interferon-gamma, and LPS induced viperin expression. Conclusion-Viperin is expressed in atherosclerosis and induced in vascular cells by inflammatory stimuli and cytomegalovirus infection. The putative functions of viperin in atherosclerosis may relate to disease-associated microbes.

  • 11.
    Paloschi, Valentina
    et al.
    Karolinska Institutet, Stockholm, Sweden.
    Kurtovic, Sanela
    Karolinska Institutet, Stockholm, Sweden.
    Folkersen, Lasse
    Karolinska Institutet, Stockholm, Sweden.
    Gomez, Delphine
    University of Paris 07, France .
    Wågsäter, Dick
    Karolinska Institutet, Stockholm, Sweden.
    Roy, Joy
    Karolinska Institutet, Stockholm, Sweden.
    Petrini, Johan
    Karolinska Institutet, Stockholm, Sweden.
    Eriksson, Maria J.
    Karolinska Institutet, Stockholm, Sweden.
    Caidahl, Kenneth
    Karolinska Institutet, Stockholm, Sweden.
    Hamsten, Anders
    Karolinska Institutet, Stockholm, Sweden.
    Liska, Jan
    Karolinska Institutet, Stockholm, Sweden.
    Michel, Jean-Baptiste
    University of Paris 07, France .
    Franco-Cereceda, Anders
    Karolinska Institutet, Stockholm, Sweden.
    Eriksson, Per
    Karolinska Institutet, Stockholm, Sweden.
    Impaired Splicing of Fibronectin Is Associated With Thoracic Aortic Aneurysm Formation in Patients With Bicuspid Aortic Valve2011In: Arteriosclerosis, Thrombosis and Vascular Biology, ISSN 1079-5642, E-ISSN 1524-4636, Vol. 31, no 3, p. 691-697Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE:

    Thoracic aortic aneurysm is a common complication in patients with bicuspid aortic valve (BAV). Alternatively spliced extra domain A (EDA) of fibronectin (FN) has an essential role in tissue repair. Here we analyze the expression of FN spliceforms in dilated and nondilated ascending aorta of tricuspid aortic valve (TAV) and BAV patients.

    METHODS AND RESULTS:

    The mRNA expression was analyzed in the ascending aorta by Affymetrix Exon arrays in patients with TAV (n=40) and BAV (n=69). EDA and extra domain B (EDB) expression was increased in dilated aorta from TAV patients compared with nondilated aorta (P<0.001 and P<0.05, respectively). In contrast, EDA expression was not increased in dilated aorta from BAV patients (P=0.25), whereas EDB expression was upregulated (P<0.01). The expression of EDA correlated with maximum aortic diameter in TAV (ρ=0.58) but not in BAV (ρ=0.15) patients. Protein analyses of EDA-FN showed concordant results. Transforming growth factor-β treatment influenced the splicing of FN and enhanced the formation of EDA-containing FN in cultured medial cells from TAV patients but not in cells derived from BAV patients. Gene set enrichment analysis together with multivariate and univariate data analyses of mRNA expression suggested that differences in the transforming growth factor-β signaling pathway may explain the impaired EDA inclusion in BAV patients.

    CONCLUSIONS:

    Decreased EDA expression may contribute to increased aneurysm susceptibility of BAV patients.

  • 12.
    Smedby, Örjan
    Department of Diagnostic Radiology, Uppsala University, Sweden.
    Do plaques grow upstream or downstream?: an angiographic study in the femoral artery.1997In: Arteriosclerosis, Thrombosis and Vascular Biology, ISSN 1079-5642, E-ISSN 1524-4636, Vol. 17, no 5, p. 912-918Article in journal (Refereed)
    Abstract [en]

    Although the distribution of atherosclerosis has been described, little is known about the direction of growth of plaques. In this study, 237 patients with slight or moderate atherosclerosis underwent femoral angiography twice at a 3-year interval, and the films were studied with computerized image analysis. First, atherosclerosis was measured as edge roughness, and the change in roughness of each 1-cm segment over the 3-year period was related to the edge roughness of the segments immediately upstream and downstream. On the medial side of the artery, the change in edge roughness was found to be more strongly related to the roughness values upstream than to those downstream of the segment studied. This suggests that growth in the downstream direction is more common than growth in the upstream direction. On the lateral side, more equivocal results were obtained. Atherosclerosis was also assessed by study of the cross-sectional area of the artery as a function of distance along the vessel. A mathematical model of plaque growth was formulated as a nonlinear filtering of this curve. Growth in the downstream direction was significantly (P<.001) more frequent than growth in the upstream direction. The findings are compatible with an atherogenic effect of fluid mechanical disturbances, such as flow separation, that may occur downstream of a stenosis.

  • 13.
    Smedby, Örjan
    et al.
    Department of Diagnostic Radiology, Uppsala University.
    Johansson, J
    Mölgaard, J
    Olsson, A G
    Walldius, G
    Erikson, U
    Predilection of atherosclerosis for the inner curvature in the femoral artery: A digitized angiography study1995In: Arteriosclerosis, Thrombosis and Vascular Biology, ISSN 1079-5642, E-ISSN 1524-4636, Vol. 15, no 7, p. 912-917Article in journal (Refereed)
    Abstract [en]

    The degree of atherosclerosis in the inner and outer curvature of the femoral artery was studied by using digitized angiography and edge-roughness calculations in 301 hyperlipidemic patients. When the two edges of the vessel were compared no significant difference was seen, but when the local curvature was taken into account, inner curves were found to be more atherosclerotic than outer curves, and both inner and outer curves were more affected than straight segments. The same pattern was encountered in subpopulations defined by clinical or blood lipid criteria. The suggested explanation is that flow disturbances such as low shear rates or separated flow, which tend to arise along the inner curvature, promote the development of atherosclerosis.

  • 14.
    Wuttge, Dirk M.
    et al.
    Karolinska Institute, Stockholm, Sweden.
    Zhou, Xinghua
    Karolinska Institute, Stockholm, Sweden.
    Sheikine, Yuri
    Karolinska Institute, Stockholm, Sweden.
    Wågsäter, Dick
    University of Örebro, Sweden .
    Stemme, Veronika
    Karolinska Institute, Stockholm, Sweden.
    Hedin, Ulf
    Karolinska Institute, Stockholm, Sweden.
    Stemme, Sten
    Karolinska Institute, Stockholm, Sweden.
    Hansson, Göran K.
    Karolinska Institute, Stockholm, Sweden.
    Sirsjö, Allan
    University of Örebro, Sweden.
    CXCL16/SR-PSOX is an interferon-gamma-regulated chemokine and scavenger receptor expressed in atherosclerotic lesions2004In: Arteriosclerosis, Thrombosis and Vascular Biology, ISSN 1079-5642, E-ISSN 1524-4636, Vol. 24, no 4, p. 750-755Article in journal (Refereed)
    Abstract [en]

    Objective-Atherosclerosis is an inflammatory disease. Several chemokines are important for monocyte/macrophage and T-cell recruitment to the lesion. CXCL16 is a recently discovered chemokine that is expressed in soluble and transmembrane forms, ligates CXCR6 chemokine receptor, and guides migration of activated Th1 and Tc1 cells. It is identical to scavenger receptor SR-PSOX, which mediates uptake of oxidized low-density lipoprotein. We investigated whether CXCL16 expression is controlled by interferon-gamma (IFN-gamma)-cytokine abundant in atherosclerotic lesions. Methods and Results-CXCL16 and CXCR6 expression was identified by polymerase chain reaction and histochemistry in atherosclerotic lesions from humans and apolipoprotein-E-deficient mice. In vitro IFN-gamma induced CXCL16 in human monocytic THP-1 cells and primary human monocytes, which led to increased uptake of oxidized low-density lipoprotein in THP-1 cells, which could be blocked by peptide antibodies against CXCL16. In vivo IFN-gamma induced CXCL16 expression in murine atherosclerotic lesions. Conclusions-We demonstrate a novel role of IFN-gamma in foam cell formation through upregulation of CXCL16/SR-PSOX. CXCR6 expression in the plaque confirms the presence of cells able to respond to CXCL16. Therefore, this chemokine/scavenger receptor could serve as a molecular link between lipid metabolism and immune activity in the atherosclerotic lesion.

  • 15.
    Yuan, XiMing
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Experimental Pathology. Linköping University, Faculty of Health Sciences.
    Brunk, Ulf
    Linköping University, Department of Medicine and Health Sciences, Pharmacology. 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.
    Effects of iron- and hemoglobin-loaded human monocyte-derived macrophages on oxidation and uptake of LDL1995In: Arteriosclerosis, Thrombosis and Vascular Biology, ISSN 1079-5642, E-ISSN 1524-4636, Vol. 15, no 9, p. 1345-51Article in journal (Refereed)
    Abstract [en]

    It is generally accepted that transition metals are required for cellular LDL oxidation. LDL may also be oxidized by iron and reducing agents in cell-free systems. We hypothesized that lysosomal iron may be exocytosed from macrophages that have been iron loaded by phagocytosis and degradation of iron-rich structures, eg, erythrocytes, and that such released iron may promote LDL oxidation and uptake by macrophages. Human monocyte-derived macrophages (HMDMs) were isolated and cultured for 7 days and then exposed to FeCl3, Fe-ADP, or Fe-EDTA (100 mumol/L) or hemoglobin (25 or 50 micrograms/mL) for 24 hours. After rinsing, LDL (50 to 150 micrograms/mL) was added in fresh culture medium without serum. After another 24 hours the media concentrations of iron and thiobarbituric acid-reacting substances as well as the electrophoretic mobility of LDL were increased, while the cells showed only minimal signs of decreased viability. Lipofuscin, neutral lipids, and phospholipids accumulated in a granular, lysosome-like pattern, and the cells acquired a foam cell-like morphology. There was a strong correlation (r = .87, P = .005) between the amount of iron added during the pre-exposure period and lipofuscin accumulation during the ensuing exposure to LDL in fresh, serum-free medium. Our results support our hypothesis and indicate that lysosomal iron may be exocytosed from HMDMs and promote oxidation and uptake of LDL and thus induce foam cell formation.

  • 16.
    Zidén, Bo
    et al.
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Medicine and Care, Internal Medicine. Östergötlands Läns Landsting, MKC-2, GE: endomed.
    Kaminkas, A
    Kristensson, Margareta
    Linköping University, Faculty of Health Sciences. Linköping University, Department of health and environment. Östergötlands Läns Landsting, FHVC - Folkhälsovetenskapligt centrum, Förebygg.med.
    Kucinskiene, Z
    Vessby, B
    Olsson, Anders
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Medicine and Care, Internal Medicine. Östergötlands Läns Landsting, MKC-2, GE: endomed.
    Diczfaluzy, U
    Increased plasma 7B-hydroxycholesterol concentrations in a population with high risk for cardiovascular disease.1999In: Arteriosclerosis, Thrombosis and Vascular Biology, ISSN 1079-5642, E-ISSN 1524-4636, Vol. 19, p. 967-971Article in journal (Refereed)
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