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  • 1.
    Brunk, Ulf
    et al.
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Medicine and Health Sciences, Pharmacology .
    Yu, ZQ
    Persson, Lennart
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Experimental Pathology . Östergötlands Läns Landsting, Centre of Surgery and Oncology, Department of Respiratory Medicine UHL.
    Eaton, John Wallace
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Experimental Pathology . Östergötlands Läns Landsting, Centre for Laboratory Medicine, Department of Clinical Pathology and Clinical Genetics.
    Lysosomes, iron and oxidative stress2003In: Free radical research, ISSN 1071-5762, E-ISSN 1029-2470, Vol. 37, p. 34-34Conference paper (Other academic)
  • 2.
    Gao, X.
    et al.
    Molecular Targets Group, J. G. Brown Cancer Center, University of Louisville, Louisville, KY 40202, United States, Department of Oncology, Institute of Biomedicine and Surgery, University of Linköping, Linköping, 58185, Sweden.
    Qian, M.
    Molecular Targets Group, J. G. Brown Cancer Center, University of Louisville, Louisville, KY 40202, United States.
    Campian, J.L.
    Molecular Targets Group, J. G. Brown Cancer Center, University of Louisville, Louisville, KY 40202, United States.
    Clark, D.R.
    Molecular Targets Group, J. G. Brown Cancer Center, University of Louisville, Louisville, KY 40202, United States, Department of Pharmacology and Toxicology, University of Louisville, Louisville, KY 40202, United States.
    Burke, T.J.
    Department of Pharmacology and Toxicology, University of Louisville, Louisville, KY 40202, United States.
    Eaton, John Wallace
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Experimental Pathology . Östergötlands Läns Landsting, Centre for Laboratory Medicine, Department of Clinical Pathology and Clinical Genetics.
    McGregor, W.G.
    Molecular Targets Group, J. G. Brown Cancer Center, University of Louisville, Louisville, KY 40202, United States, Department of Pharmacology and Toxicology, University of Louisville, Louisville, KY 40202, United States, Center for Genetics and Molecular Medicine, University of Louisville, Louisville, KY 40202, United States.
    Cytotoxic and mutagenic effects of tobacco-borne free fatty acids2006In: Free Radical Biology & Medicine, ISSN 0891-5849, E-ISSN 1873-4596, Vol. 40, no 1, p. 165-172Article in journal (Refereed)
    Abstract [en]

    Tobacco smoke contains substances capable of binding iron in an aqueous medium and transferring the metal into both organic solvents and intact mammalian red cells. This iron-binding activity is due to free fatty acids which are abundant in tobacco smoke and form 2:1 (free fatty acid:iron) chelates with ferrous iron. These earlier observations suggested that smoke-borne free fatty acids and the associated delocalization of iron within the lung might contribute to both the chronic pulmonary inflammation and the carcinogenesis associated with smoking. We now report that micromolar concentrations of iron or free fatty acid are not toxic to cultured human lung fibroblasts. However, when combined, the same low concentrations of iron and free fatty acid exert synergistic toxicity. Furthermore, the combination of free fatty acid and iron is highly mutagenic, inducing almost as many selectable mutations in the gene for hypoxanthine/guanine phosphoribosyl transferase as does benzo[a] pyrenediolepoxide, a class I carcinogen generated from benzo[a]pyrene present in cigarette smoke. The combination of free fatty acid and iron also promotes transformation of NIH 3T3 cells into an anchorage-independent phenotype. We conclude that free fatty acids in tobacco smoke may be important contributors to both the pulmonary damage and the carcinogenesis associated with smoking. © 2005 Elsevier Inc. All rights reserved.

  • 3.
    Gao, Xueshan
    et al.
    University of Louisville.
    Li Campian, Jian
    University of Louisville.
    Qian, Mingwei
    University of Louisville.
    Sun, Xiao-Feng
    Linköping University, Department of Clinical and Experimental Medicine, Oncology . Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre of Surgery and Oncology, Department of Oncology UHL.
    Wallace Eaton, John
    Linköping University, Department of Clinical and Experimental Medicine, Experimental Pathology . Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Laboratory Medicine, Department of Clinical Pathology and Clinical Genetics.
    Mitochondrial DNA Damage in Iron Overload2009In: JOURNAL OF BIOLOGICAL CHEMISTRY, ISSN 0021-9258, Vol. 284, no 8, p. 4767-4775Article in journal (Refereed)
    Abstract [en]

    Chronic iron overload has slow and insidious effects on heart, liver, and other organs. Because iron-driven oxidation of most biologic materials (such as lipids and proteins) is readily repaired, this slow progression of organ damage implies some kind of biological "memory." We hypothesized that cumulative iron-catalyzed oxidant damage to mtDNA might occur in iron overload, perhaps explaining the often lethal cardiac dysfunction. Real time PCR was used to examine the " intactness" of mttDNA in cultured H9c2 rat cardiac myocytes. After 3 -5 days exposure to high iron, these cells exhibited damage to mtDNA reflected by diminished amounts of near full-length 15.9-kb PCR product with no change in the amounts of a 16.1-kb product from a nuclear gene. With the loss of intact mtDNA, cellular respiration declined and mRNAs for three electron transport chain subunits and 16 S rRNA encoded by mtDNA decreased, whereas no decrements were found in four subunits encoded by nuclear DNA. To examine the importance of the interactions of iron with metabolically generated reactive oxygen species, we compared the toxic effects of iron in wild-type and rhoo cells. In wild-type cells, elevated iron caused increased production of reactive oxygen species, cytostasis, and cell death, whereas the rhoo cells were unaffected. We conclude that long-term damage to cells and organs in iron-overload disorders involves interactions between iron and mitochondrial reactive oxygen species resulting in cumulative damage to mtDNA, impaired synthesis of respiratory chain subunits, and respiratory dysfunction.

  • 4.
    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.

  • 5.
    Li, Wei
    et al.
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Medicine and Health Sciences.
    Yuan, Ximing
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine.
    Ivanova, S.
    Laboratory of Biomedical Science, North Shore-LIE Research Institute, Manhasset, NY 11030, United States.
    Tracey, K.J.
    Laboratory of Biomedical Science, North Shore-LIE Research Institute, Manhasset, NY 11030, United States.
    Eaton, John Wallace
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Experimental Pathology . Östergötlands Läns Landsting, Centre for Laboratory Medicine, Department of Clinical Pathology and Clinical Genetics.
    Brunk, Ulf
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Medicine and Health Sciences, Pharmacology .
    3-Aminopropanal, formed during cerebral ischaemia, is a potent lysosomotropic neurotoxin2003In: Biochemical Journal, ISSN 0264-6021, E-ISSN 1470-8728, Vol. 371, no 2, p. 429-436Article in journal (Refereed)
    Abstract [en]

    Cytotoxic polyamine-derived amino aldehydes, formed during cerebral ischaemia, damage adjacent tissue (the so-called 'penumbra') not subject to the initial ischaemic insult. One such product is 3-aminopropanal (3-AP), a potent cytotoxin that accumulates in ischaemic brain, although the precise mechanisms responsible for its formation are still unclear. More relevant to the present investigations, the mechanisms by which such a small aldehydic compound might be cytotoxic are also not known, but we hypothesized that 3-AP, having the structure of a weak lysosomotropic base, might concentrate within lysosomes, making these organelles a probable focus of initial toxicity. Indeed, 3-AP leads to lysosomal rupture of D384 glioma cells, a process which clearly precedes caspase activation and apoptotic cell death. Immunohistochemistry reveals that 3-AP concentrates in the lysosomal compartment and prevention of this accumulation by the lysosomotropic base ammonia, NH3, protects against 3-AP cytotoxicity by increasing lysosomal pH. A thiol compound, N-(2-mercaptopropionyl)glycine, reacts with and neutralizes 3-AP and significantly inhibits cytoxocity. Both amino and aldehyde functions of 3-AP are necessary for toxicity: the amino group confers lysosomotropism and the aldehyde is important for additional, presently unknown, reactions. We conclude that 3-AP exerts its toxic effects by accumulating intralysosomally, causing rupture of these organelles and releasing lysosomal enzymes which initiate caspase activation and apoptosis (or necrosis if the lysosomal rupture is extensive). These results may have implications for the development of new therapeutics designed to lessen secondary damage arising from focal cerebral ischaemia.

  • 6.
    Neuzil, Jiri
    et al.
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Neuroscience and Locomotion, Pathology.
    Zhao, Ming
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Neuroscience and Locomotion, Pathology.
    Ostermann, Georg
    Sticha, Martin
    Gellert, Nina
    Weber, Christian
    Eaton, John Wallace
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Neuroscience and Locomotion, Pathology. Östergötlands Läns Landsting, Centre for Laboratory Medicine, Department of Clinical Pathology and Clinical Genetics.
    Brunk, Ulf
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Neuroscience and Locomotion, Pathology. Östergötlands Läns Landsting, Centre for Laboratory Medicine, Department of Clinical Pathology and Clinical Genetics.
    Alfa-Tocopheryl succinate, an agent with in vivo anti-tumour activity, induces apoptosis by causing lysosomal instability2002In: Biochemical Journal, ISSN 0264-6021, E-ISSN 1470-8728, Vol. 362, p. 709-715Article in journal (Refereed)
  • 7.
    Persson, H.Lennart
    et al.
    Linköping University, Department of Neuroscience and Locomotion, Pathology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre of Surgery and Oncology, Department of Respiratory Medicine.
    Kurz, Tino
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Medicine and Health Sciences, Pharmacology .
    Eaton, John Wallace
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Experimental Pathology . Östergötlands Läns Landsting, Centre for Laboratory Medicine, Department of Clinical Pathology and Clinical Genetics.
    Brunk, Ulf
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Medicine and Health Sciences, Pharmacology .
    Radiation-induced cell death: Importance of lysosomal destabilization2005In: Biochemical Journal, ISSN 0264-6021, E-ISSN 1470-8728, Vol. 389, no 3, p. 877-884Article in journal (Refereed)
    Abstract [en]

    The mechanisms involved in radiation-induced cellular injury and death remain incompletely understood. In addition to the direct formation of highly reactive hydroxyl radicals (HO.) by radiolysis of water, oxidative stress events in the cytoplasm due to formation of H2O2 may also be important. Since the major pool of low-mass redox-active intracellular iron seems to reside within lysosomes, arising from the continuous intralysosomal autophagocytotic degradation of ferruginous materials, formation of H2O2 inside and outside these organelles may cause lysosomal labilization with release to the cytosol of lytic enzymes and low-mass iron. If of limited magnitude, such release may induce 'reparative autophagocytosis', causing additional accumulation of redox-active iron within the lysosomal compartment. We have used radio-resistant histiocytic lymphoma (J774) cells to assess the importance of intralysosomal iron and lysosomal rupture in radiation-induced cellular injury. We found that a 40 Gy radiation dose increased the 'loose' iron content of the (still viable) cells approx. 5-fold when assayed 24 h later. Cytochemical staining revealed that most redox-active iron was within the lysosomes. The increase of intralysosomal iron was associated with 'reparative autophagocytosis', and sensitized cells to Iysosomal rupture and consequent apoptotic/necrotic death following a second, much lower dose of radiation (20 Gy) 24 h after the first one. A high-molecular-mass derivative of desferrioxamine, which specifically localizes intralysosomally following endocytic uptake, added to the culture medium before either the first or the second dose of radiation, stabilized lysosomes and largely prevented cell death. These observations may provide a biological rationale for fractionated radiation. © 2005 Biochemical Society.

  • 8.
    Persson, Lennart
    et al.
    Linköping University, Department of Neuroscience and Locomotion, Pathology. Linköping University, Department of Medicine and Care, Pulmonary Medicine. Linköping University, Faculty of Health Sciences.
    Eaton, John Wallace
    Linköping University, Department of Neuroscience and Locomotion, Pathology. Linköping University, Faculty of Health Sciences.
    Brunk, Ulf
    Linköping University, Department of Neuroscience and Locomotion, Pathology. Linköping University, Faculty of Health Sciences.
    Chelation of intralysosomal redox-active iron protects against ionizing radiation damageManuscript (preprint) (Other academic)
    Abstract [en]

    The mechanisms involved in cellular injury and death caused by ionizing radiation remain incompletely understood. Although DNA damage - especially to actively dividing cells - is certainly a critical component, other types of damage may also be important. Ionizing radiation generates reactive oxygen species (ROS) and 'loose' (i.e., redox-active) iron amplifies the damaging effects of ROS. The major pool of reactive intracellular iron may reside within the acidic vacuolar compartment (lysosomes and late endosomes). Lysosomes are responsible for the continuous digestion of ferruginous materials such as fenitin, mitochondria, and various metalloproteins. We have investigated the possible importance of intralysosomal iron and lysosomal rupture in radiation-induced cellular injury using macrophage-like J774 cells. We find: (i) Gamma radiation of cells greatly enhances the intracellular pool of reactive iron, which increase ≈ 5-fold 24 hours following a non-lethal single dose of radiation (40 Gy). (ii) Using a special staining procedure (the sulfide-silver method or auto-metallography), we find that most redox-active iron resides within the lysosomal compartment both before and after radiation. The dramatically increased intralysosomal iron following radiation probably derives from reparatin· autophagocytosis, whereby damaged iron-containing cellular constituents are digested intralysosomally. (iii) This increased lysosomal iron sensitizes cells to a second dose of radiation (20 Gy), which results in lysosomal rupture and ensuing apoptosis or necrosis. The enhanced sensitivity to radiation-induced lysosomal rupture is very likely linked to lysosomal iron: two chemically distinct iron chelators, HMW-DFO and LAP, which specifically localize within the lysosomal compartment, stabilize lysosomes and prevent cell death. These observations provide a biological rationale for fractionated radiation, in that a primary dose of radiation causes increased intralysosomal iron and synergizes the damage from a second dose of radiation. The resultant lysosomal rupture may not only lead directly to cell death, as we have proposed elsewhere, but iron released from lysosomes may relocate to the nucleus, intensifying radiation-mediated DNA damage. These findings should be useful in the design of more effective regimens of fractionated radiation and in designing new therapeutic modalities for the prevention of incidental radiationinduced death of normal tissues.

  • 9.
    Persson, Lennart
    et al.
    Linköping University, Department of Neuroscience and Locomotion, Pathology. Linköping University, Department of Medicine and Care, Pulmonary Medicine. Linköping University, Faculty of Health Sciences.
    Yu, Zhengquan
    Linköping University, Department of Neuroscience and Locomotion, Pathology. Linköping University, Department of Neuroscience and Locomotion, Neurosurgery. Linköping University, Faculty of Health Sciences.
    Tirosh, Oren
    Institute of Biochemistry, Food Science and Nutrition, Faculty of Agricultural, Food and Environmental Quality Sciences, The Hebrew University of Jerusalem, Jerusalem, Israel.
    Eaton, John Wallace
    Linköping University, Department of Neuroscience and Locomotion, Pathology. Linköping University, Faculty of Health Sciences.
    Brunk, Ulf
    Linköping University, Department of Neuroscience and Locomotion, Pathology. Linköping University, Faculty of Health Sciences.
    Prevention of oxidant-induced cell death by lysosomotropic iron chelators2003In: Free Radical Biology & Medicine, ISSN 0891-5849, E-ISSN 1873-4596, Vol. 34, no 10, p. 1295-1305Article in journal (Refereed)
    Abstract [en]

    Intralysosomal iron powerfully synergizes oxidant-induced cellular damage. The iron chelator, desferrioxamine (DFO), protects cultured cells against oxidant challenge but pharmacologically effective concentrations of this drug cannot readily be achieved in vivo. DFO localizes almost exclusively within the lysosomes following endocytic uptake, suggesting that truly lysosomotropic chelators might be even more effective. We hypothesized that an amine derivative of α-lipoamide (LM), 5-[1,2] dithiolan-3-yl-pentanoic acid (2-dimethylamino-ethyl)-amide (α-lipoic acid-plus [LAP]; pKa = 8.0), would concentrate via proton trapping within lysosomes, and that the vicinal thiols of the reduced form of this agent would interact with intralysosomal iron, preventing oxidant-mediated cell damage. Using a thiol-reactive fluorochrome, we find that reduced LAP does accumulate within the lysosomes of cultured J774 cells. Furthermore, LAP is approximately 1,000 and 5,000 times more effective than LM and DFO, respectively, in protecting lysosomes against oxidant-induced rupture and in preventing ensuing apoptotic cell death. Suppression of lysosomal accumulation of LAP (by ammonium-mediated lysosomal alkalinization) blocks these protective effects. Electron paramagnetic resonance reveals that the intracellular generation of hydroxyl radical following addition of hydrogen peroxide to J774 cells is totally eliminated by pretreatment with either DFO (1 mM) or LAP (0.2 μM) whereas LM (200 μM) is much less effective.

  • 10.
    Telang, S
    et al.
    Baylor Coll Med, Dept Ped, Houston, TX 77030 USA Calif State Univ Los Angeles, Dept Biol, Chico, CA 95929 USA Linkoping Univ, Div Path, Linkoping, Sweden.
    Mahoney, J
    Baylor Coll Med, Dept Ped, Houston, TX 77030 USA Calif State Univ Los Angeles, Dept Biol, Chico, CA 95929 USA Linkoping Univ, Div Path, Linkoping, Sweden.
    Law, I
    Baylor Coll Med, Dept Ped, Houston, TX 77030 USA Calif State Univ Los Angeles, Dept Biol, Chico, CA 95929 USA Linkoping Univ, Div Path, Linkoping, Sweden.
    Lundqvist-Gustafsson, H
    Baylor Coll Med, Dept Ped, Houston, TX 77030 USA Calif State Univ Los Angeles, Dept Biol, Chico, CA 95929 USA Linkoping Univ, Div Path, Linkoping, Sweden.
    Qian, M
    Baylor Coll Med, Dept Ped, Houston, TX 77030 USA Calif State Univ Los Angeles, Dept Biol, Chico, CA 95929 USA Linkoping Univ, Div Path, Linkoping, Sweden.
    Eaton, John Wallace
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Experimental Pathology . Östergötlands Läns Landsting, Centre for Laboratory Medicine, Department of Clinical Pathology and Clinical Genetics.
    Iron dependent virulence in E. coli - A strain specific phenomenon2000In: The FASEB Journal, ISSN 0892-6638, E-ISSN 1530-6860, Vol. 14, no 4, p. A280-A280Conference paper (Other academic)
  • 11.
    Telang, S
    et al.
    Univ Louisville, James Graham Brown Canc Ctr, Louisville, KY 40202 USA Baylor Coll Med, Dept Pediat, Houston, TX 77030 USA Univ Illinois, Dept Pathobiol, Urbana, IL 61801 USA Calif State Univ Chico, Dept Biol, Chico, CA USA Linkoping Univ, Fac Hlth Sci, Div Pathol 2, Linkoping, Sweden.
    Vimr, E
    Univ Louisville, James Graham Brown Canc Ctr, Louisville, KY 40202 USA Baylor Coll Med, Dept Pediat, Houston, TX 77030 USA Univ Illinois, Dept Pathobiol, Urbana, IL 61801 USA Calif State Univ Chico, Dept Biol, Chico, CA USA Linkoping Univ, Fac Hlth Sci, Div Pathol 2, Linkoping, Sweden.
    Mahoney, JR
    Univ Louisville, James Graham Brown Canc Ctr, Louisville, KY 40202 USA Baylor Coll Med, Dept Pediat, Houston, TX 77030 USA Univ Illinois, Dept Pathobiol, Urbana, IL 61801 USA Calif State Univ Chico, Dept Biol, Chico, CA USA Linkoping Univ, Fac Hlth Sci, Div Pathol 2, Linkoping, Sweden.
    Law, I
    Univ Louisville, James Graham Brown Canc Ctr, Louisville, KY 40202 USA Baylor Coll Med, Dept Pediat, Houston, TX 77030 USA Univ Illinois, Dept Pathobiol, Urbana, IL 61801 USA Calif State Univ Chico, Dept Biol, Chico, CA USA Linkoping Univ, Fac Hlth Sci, Div Pathol 2, Linkoping, Sweden.
    Lundqvist-Gustafsson, H
    Univ Louisville, James Graham Brown Canc Ctr, Louisville, KY 40202 USA Baylor Coll Med, Dept Pediat, Houston, TX 77030 USA Univ Illinois, Dept Pathobiol, Urbana, IL 61801 USA Calif State Univ Chico, Dept Biol, Chico, CA USA Linkoping Univ, Fac Hlth Sci, Div Pathol 2, Linkoping, Sweden.
    Qian, MW
    Univ Louisville, James Graham Brown Canc Ctr, Louisville, KY 40202 USA Baylor Coll Med, Dept Pediat, Houston, TX 77030 USA Univ Illinois, Dept Pathobiol, Urbana, IL 61801 USA Calif State Univ Chico, Dept Biol, Chico, CA USA Linkoping Univ, Fac Hlth Sci, Div Pathol 2, Linkoping, Sweden.
    Eaton, John Wallace
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Experimental Pathology . Östergötlands Läns Landsting, Centre for Laboratory Medicine, Department of Clinical Pathology and Clinical Genetics.
    Strain-specific iron-dependent virulence in Escherichia coli2001In: Journal of Infectious Diseases, ISSN 0022-1899, E-ISSN 1537-6613, Vol. 184, no 2, p. 159-165Article in journal (Refereed)
    Abstract [en]

    For reasons unknown, certain Escherichia coli strains become highly virulent when injected with hemoglobin or other soluble iron sources. Two clinical isolates (virulent and nonvirulent) showed equivalent hemoglobin-mediated growth acceleration in vitro. However, when injected intraperitoneally into mice without hemoglobin, the virulent strain was cleared more slowly (t(1/2), >4 h vs. <30 min). The virulent E. coli strain had a polysialic acid-containing capsule, whereas the nonvirulent strain did not. Virulent E. coli grown at 20C (which blocks polysialylation) were cleared as rapidly as nonvirulent organisms. In another virulent E. coli strain having abundant outer membrane polysialic acid, targeted deletion of the polysialyltransferase accelerated host clearance and blocked iron-dependent virulence. The iron-dependent virulence of certain E. coli strains may represent the combined effect of slow in vivo clearance-associated, in this case, with outer membrane polysialylation coupled with accelerated growth permitted by iron compounds.

  • 12.
    Terman, Alexei
    et al.
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Neuroscience and Locomotion, Pathology.
    Dalen, Helge
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Neuroscience and Locomotion, Pathology. Östergötlands Läns Landsting, Centre for Laboratory Medicine, Department of Clinical Pathology and Clinical Genetics.
    Eaton, John Wallace
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Neuroscience and Locomotion, Pathology. Östergötlands Läns Landsting, Centre for Laboratory Medicine, Department of Clinical Pathology and Clinical Genetics.
    Neuzil, Jiri
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Neuroscience and Locomotion, Pathology.
    Brunk, Ulf
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Neuroscience and Locomotion, Pathology. Östergötlands Läns Landsting, Centre for Laboratory Medicine, Department of Clinical Pathology and Clinical Genetics.
    Mitochondrial recycling and aging of cardiac myocytes: The role of autophagocytosis2003In: Experimental Gerontology, ISSN 0531-5565, E-ISSN 1873-6815, Vol. 38, no 8, p. 863-876Article in journal (Refereed)
    Abstract [en]

    The mechanisms of mitochondrial alterations in aged post-mitotic cells, including formation of so-called 'giant' mitochondria, are poorly understood. To test whether these large mitochondria might appear due to imperfect autophagic mitochondrial turnover, we inhibited autophagocytosis in cultured neonatal rat cardiac myocytes with 3-methyladenine. This resulted in abnormal accumulation of mitochondria within myocytes, loss of contractility, and reduced survival time in culture. Unlike normal aging, which is associated with slow accumulation of predominantly large defective mitochondria, pharmacological inhibition of autophagy caused only moderate accumulation of large (senescent-like) mitochondria but dramatically enhanced the numbers of small mitochondria, probably reflecting their normally more rapid turnover. Furthermore, the 3-methyladenine-induced accumulation of large mitochondria was irreversible, while small mitochondria gradually decreased in number after withdrawal of the drug. We, therefore, tentatively conclude that large mitochondria selectively accumulate in aging post-mitotic cells because they are poorly autophagocytosed. Mitochondrial enlargement may result from impaired fission, a possibility supported by depressed DNA synthesis in large mitochondria. Nevertheless, enlarged mitochondria retained immunoreactivity for cytochrome c oxidase subunit 1, implying that mitochondrial genes remain active in defective mitochondria. Our findings suggest that imperfect autophagic recycling of these critical organelles may underlie the progressive mitochondrial damage, which characterizes aging post-mitotic cells.

  • 13.
    Terman, Alexei
    et al.
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Geriatric .
    Dalen, Helge
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Experimental Pathology .
    Eaton, John Wallace
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Experimental Pathology . Östergötlands Läns Landsting, Centre for Laboratory Medicine, Department of Clinical Pathology and Clinical Genetics.
    Neuzil, Jiri
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Experimental Pathology .
    Brunka, UT
    Aging of cardiac myocytes in culture - Oxidative stress, lipofuscin accumulation, and mitochondrial turnover2004In: Annals of the New York Academy of Sciences, ISSN 0077-8923, E-ISSN 1749-6632, Vol. 1019, p. 70-77Article in journal (Refereed)
    Abstract [en]

    Oxidative stress is believed to be an important contributor to aging, mainly affecting long-lived postmitotic cells such as cardiac myocytes and neurons. Aging cells accumulate functionally effete, often mutant and enlarged mitochondria, as well as an intralysosomal undegradable pigment, lipofuscin. To provide better insight into the role of oxidative stress, mitochondrial damage, and lipofuscinogenesis in postmitotic aging, we studied the relationship between these parameters in cultured neonatal rat cardiac myocytes. It was found that the content of lipofuscin, which varied drastically between cells, positively correlated with mitochondrial damage (evaluated by decreased innermembrane potential), as well as with the production of reactive oxygen species. These results suggest that both lipofuscin accumulation and mitochondrial damage have common underlying mechanisms, likely including imperfect autophagy and ensuing lysosomal degradation of oxidatively damaged mitochondria and other organelles. Increased size of mitochondria (possibly resulting from impaired fission due to oxidative damage to mitochondrial DNA, membranes, and proteins) also may interfere with mitochondrial turnover, leading to the appearance of so-called "giant" mitochondria. This assumption is based on our observation that pharmacological inhibition of autophagy with 3-methyladenine induced only moderate accumulation of large (senescent-like) mitochondria but drastically increased numbers of small, apparently normal mitochondria, reflecting their rapid turnover and suggesting that enlarged mitochondria are poorly autophagocytosed. Overall, our findings emphasize the importance of mitochondrial turnover in postmitotic aging and provide further support for the mitochondrial-lysosomal axis theory of aging.

  • 14.
    Wearden, ME
    et al.
    Baylor Coll Med, Houston, TX 77030 USA Linkoping Univ Hosp, S-58185 Linkoping, Sweden.
    Brunk, Ulf
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Medicine and Health Sciences, Pharmacology .
    Terman, Alexei
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Geriatric .
    Eaton, John Wallace
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Experimental Pathology . Östergötlands Läns Landsting, Centre for Laboratory Medicine, Department of Clinical Pathology and Clinical Genetics.
    Mitochondria: Potential importance in hyperoxic lung injury2000In: Pediatric Research, ISSN 0031-3998, E-ISSN 1530-0447, Vol. 47, no 4, p. 2244-Conference paper (Other academic)
  • 15.
    Yu, Zhengquan
    et al.
    Linköping University, Department of Neuroscience and Locomotion, Pathology. Linköping University, Department of Neuroscience and Locomotion, Neurosurgery. Linköping University, Faculty of Health Sciences.
    Eaton, John Wallace
    James Graham Brown Cancer Center, University of Louisville, Louisville, Kentucky, USA.
    Persson, Lennart
    Linköping University, Department of Neuroscience and Locomotion, Pathology. Linköping University, Department of Medicine and Care, Pulmonary Medicine. Linköping University, Faculty of Health Sciences.
    The radioprotective agent, amifostine, suppresses the reactivity of intralysosomal iron2003In: Redox report, ISSN 1351-0002, E-ISSN 1743-2928, Vol. 8, no 6, p. 347-355Article in journal (Refereed)
    Abstract [en]

    Amifostine (2-[(3-aminopropyl)amino]ethane-thiol dihydrogen phosphate ester; WR-2721) is a radioprotective agent used clinically to minimize damage from radiation therapy to adjacent normal tissues. This inorganic thiophosphate requires dephosphorylation to produce the active, cell-permeant thiol metabolite, WR-1065. The activation step is presumably catalyzed by membrane-bound alkaline phosphatase, activity of which is substantially higher in the endothelium of normal tissues. This site-specific delivery may explain the preferential protection of normal versus neoplastic tissues. Although it was developed several decades ago, the mechanisms through which this agent exerts its protective effects remain unknown. Because WR-1065 is a weak base (pKa = 9.2), we hypothesized that the drug should preferentially accumulate (via proton trapping) within the acidic environment of intracellular lysosomes. These organelles contain abundant 'loose' iron and represent a likely initial target for oxidant- and radiation-mediated damage. We further hypothesized that, within the lysosomal compartment, the thiol groups of WR-1065 would interact with this iron, thereby minimizing iron-catalyzed lysosomal damage and ensuing cell death. A similar mechanism of protection via intralysosomal iron chelation has been invoked for the hexadentate iron chelator, desferrioxamine (DFO; although DFO enters the lysosomal compartment by endocytosis, not proton trapping). Using cultured J774 cells as a model system, we found substantial accumulation of WR-1065 within intracellular granules as revealed by reaction with the thiol-binding fluorochrome, BODIPY FL L-cystine. These granules are lysosomes as indicated by co-localization of BODIPY staining with LysoTracker Red. Compared to 1 mM DFO, cells pre-treated with 0.4 ?M WR-1065 are protected from hydrogen peroxide-mediated lysosomal rupture and ensuing cell death. On a molar basis in this experimental system, WR-1065 is approximately 2500 times more effective than DFO in preventing oxidant-induced lysosomal rupture and cell death. This increased effectiveness is most likely due to the preferential concentration of this weak base within the acidic lysosomal apparatus. By electron spin resonance, we found that the generation of hydroxyl radical, which normally occurs following addition of hydrogen peroxide to J774 cells, is totally blocked by pretreatment with either WR-1065 or DFO. These findings suggest a single and plausible explanation for the radioprotective effects of amifostine and may provide a basis for the design of even more effective radio- and chemoprotective drugs.

  • 16.
    Yu, Zhengquan
    et al.
    Linköping University, Department of Neuroscience and Locomotion, Pathology. Linköping University, Department of Neuroscience and Locomotion, Neurosurgery. Linköping University, Faculty of Health Sciences.
    Persson, Lennart
    Linköping University, Department of Neuroscience and Locomotion, Pathology. Linköping University, Department of Medicine and Care, Pulmonary Medicine. Linköping University, Faculty of Health Sciences.
    Eaton, John Wallace
    Linköping University, Department of Neuroscience and Locomotion, Pathology. Linköping University, Faculty of Health Sciences.
    Brunk, Ulf
    Linköping University, Department of Neuroscience and Locomotion, Pathology. Linköping University, Faculty of Health Sciences.
    Intralysosomal iron: a major determinant of oxidant-induced cell death2003In: Free Radical Biology & Medicine, ISSN 0891-5849, E-ISSN 1873-4596, Vol. 34, no 10, p. 1243-1252Article in journal (Refereed)
    Abstract [en]

    As a result of continuous digestion of iron-containing metalloproteins, the lysosomes within normal cells contain a pool of labile, redox-active, low-molecular-weight iron, which may make these organelles particularly susceptible to oxidative damage. Oxidant-mediated destabilization of lysosomal membranes with release of hydrolytic enzymes into the cell cytoplasm can lead to a cascade of events eventuating in cell death (either apoptotic or necrotic depending on the magnitude of the insult). To assess the importance of the intralysosomal pool of redox-active iron, we have temporarily blocked lysosomal digestion by exposing cells to the lysosomotropic alkalinizing agent, ammonium chloride (NH4Cl). The consequent increase in lysosomal pH (from ca. 4.5 to > 6) inhibits intralysosomal proteolysis and, hence, the continuous flow of reactive iron into this pool. Preincubation of J774 cells with 10 mM NH4Cl for 4 h dramatically decreased apoptotic death caused by subsequent exposure to H2O2, and the protection was as great as that afforded by the powerful iron chelator, desferrioxamine (which probably localizes predominantly in the lysosomal compartment). Sulfide-silver cytochemical detection of iron revealed a pronounced decrease in lysosomal content of redox-active iron after NH4Cl exposure, probably due to diminished intralysosomal digestion of iron-containing material coupled with continuing iron export from this organelle. Electron paramagnetic resonance experiments revealed that hydroxyl radical formation, readily detectable in control cells following H2O2 addition, was absent in cells preexposed to 10 mM NH4Cl. Thus, the major pool of redox-active, low-molecular-weight iron may be located within the lysosomes. In a number of clinical situations, pharmacologic strategies that minimize the amount or reactivity of intralysosomal iron should be effective in preventing oxidant-induced cell death.

  • 17.
    Zhao, Ming
    et al.
    Linköping University, Department of Neuroscience and Locomotion, Pathology. Linköping University, Faculty of Health Sciences.
    Antunes, Fernando
    Linköping University, Department of Neuroscience and Locomotion, Pathology. Linköping University, Faculty of Health Sciences.
    Eaton, John W.
    Linköping University, Department of Neuroscience and Locomotion, Pathology. Linköping University, Faculty of Health Sciences.
    Brunk, Ulf T.
    Linköping University, Department of Neuroscience and Locomotion, Pathology. Linköping University, Faculty of Health Sciences.
    Relocation of lysosomal enzymes induces mitochondria-mediated oxidative stress, release of cytochrome c, and apoptosisManuscript (preprint) (Other academic)
    Abstract [en]

    Oxidative stress induces apoptosis, or necrosis, initiated by iron-catalyzed, intra-lysosomal oxidation leading to lysosomal rupture. Moderate lysosomal disruption induces apoptosis, while more extensive release of lysosomal contents results in necrosis. Enhanced cellular production of reactive oxygen (presumably of mitochondrial origin) also occurs during apoptosis caused by a variety of proapoptotic agonists, raising the question of whether increased oxidant generation is causal or consequential. In mixtures of rat liver lysosomes and mitochondria, selective rupture of the lysosomes by the lysosornotropic detergent 0-methyl-serine dodecylamide hydrochloride (MSDH) triggers augmented mitochondrial production of reactive oxygen species and release of cytochrome c. These mitochondrial effects are also caused by addition of purified cathepsins B and D, as well as phospholipase A2 (PLA2). We have earlier shown that PLA2 is activated by lysosomal rupture in cells undergoing apoptosis, and we now find that PLA2 - but not cathepsins B or D - causes destabilization of the membranes of semi-purified lysosomes, suggesting an amplification mechanism. In intact cultured fibroblasts, added MSDH induces lysosomal rupture, intracellular oxidant production, and apoptosis. These results suggest that initiation of the apoptotic cascade by agonists other than exogenous oxidants may involve early release of lysosomal constituents (such as cathepsins Band D) and activation of PLA2. These agents may act in concert to promote mitochondrial oxidant production, further lysosomal rupture and, finally, mitochondrial cytochrome c release. Thus, non-oxidant agonists of apoptosis may further amplify the process through oxidant mechanisms.

  • 18.
    Zhao, Ming
    et al.
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Neuroscience and Locomotion, Pathology.
    Antunes, Fernando
    Eaton, John Wallace
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Neuroscience and Locomotion, Pathology. Östergötlands Läns Landsting, Centre for Laboratory Medicine, Department of Clinical Pathology and Clinical Genetics.
    Brunk, Ulf
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Neuroscience and Locomotion, Pathology. Östergötlands Läns Landsting, Centre for Laboratory Medicine, Department of Clinical Pathology and Clinical Genetics.
    Lysosomal enzymes promote mitochondrial oxidant production, cytochrome c release and apoptosis2003In: European Journal of Biochemistry, ISSN 0014-2956, E-ISSN 1432-1033, Vol. 270, no 18, p. 3778-3786Article in journal (Refereed)
    Abstract [en]

    Exposure of mammalian cells to oxidant stress causes early (iron catalysed) lysosomal rupture followed by apoptosis or necrosis. Enhanced intracellular production of reactive oxygen species (ROS), presumably of mitochondrial origin, is also observed when cells are exposed to nonoxidant proapoptotic agonists of cell death. We hypothesized that ROS generation in this latter case might promote the apoptotic cascade and could arise from effects of released lysosomal materials on mitochondria. Indeed, in intact cells (J774 macrophages, HeLa cells and AG1518 fibroblasts) the lysosomotropic detergent O-methyl-serine dodecylamide hydrochloride (MSDH) causes lysosomal rupture, enhanced intracellular ROS production, and apoptosis. Furthermore, in mixtures of rat liver lysosomes and mitochondria, selective rupture of lysosomes by MSDH promotes mitochondrial ROS production and cytochrome c release, whereas MSDH has no direct effect on ROS generation by purifed mitochondria. Intracellular lysosomal rupture is associated with the release of (among other constituents) cathepsins and activation of phospholipase A2 (PLA2). We find that addition of purified cathepsins B or D, or of PLA2, causes substantial increases in ROS generation by purified mitochondria. Furthermore, PLA2 - but not cathepsins B or D - causes rupture of semipurified lysosomes, suggesting an amplification mechanism. Thus, initiation of the apoptotic cascade by nonoxidant agonists may involve early release of lysosomal constituents (such as cathepsins B and D) and activation of PLA2, leading to enhanced mitochondrial oxidant production, further lysosomal rupture and, finally, mitochondrial cytochrome c release. Nonoxidant agonists of apoptosis may, thus, act through oxidant mechanisms.

  • 19.
    Zhao, Ming
    et al.
    Linköping University, Department of Neuroscience and Locomotion, Pathology. Linköping University, Faculty of Health Sciences.
    Brunk, Ulf
    Linköping University, Department of Neuroscience and Locomotion, Pathology. Linköping University, Faculty of Health Sciences.
    Eaton, John Wallace
    Linköping University, Department of Neuroscience and Locomotion, Pathology. Linköping University, Faculty of Health Sciences.
    Delayed oxidant-induced cell death involves activation of phospholipase A22001In: FEBS Letters, ISSN 0014-5793, E-ISSN 1873-3468, Vol. 509, no 3, p. 399-404Article in journal (Refereed)
    Abstract [en]

    Short-term (1 h) exposure of cells to a low steady-state concentration of H2O2 causes no immediate cell death but apoptosis occurs several hours later. This delayed cell death may arise from activation of phospholipases, in particular phospholipase A2 (PLA2), which may destabilize lysosomal and mitochondrial membranes. Indeed, the secretory PLA2 (sPLA2) inhibitor 4-bromophenacyl bromide diminishes both delayed lysosomal rupture and apoptosis. Furthermore, sPLA2 activation by mellitin, or direct micro-injection of sPLA2, causes lysosomal rupture and apoptosis. Finally, B-cell leukemia/lymphoma 2 (Bcl-2) over-expression prevents oxidant-induced activation of PLA2, delayed lysosomal destabilization and apoptosis. This supports a causal association between PLA2 activation and delayed oxidant-induced cell death and suggests that Bcl-2 may suppress apoptosis by preventing PLA2 activation.

  • 20.
    Zhao, Ming
    et al.
    Linköping University, Department of Neuroscience and Locomotion, Pathology. Linköping University, Faculty of Health Sciences.
    Eaton, John Wallace
    Linköping University, Department of Neuroscience and Locomotion, Pathology. Linköping University, Faculty of Health Sciences.
    Brunk, Ulf
    Linköping University, Department of Neuroscience and Locomotion, Pathology. Linköping University, Faculty of Health Sciences.
    Bcl-2 phosphorylation is required for inhibition of oxidative stress-induced lysosomal leak and ensuing apoptosis2001In: FEBS Letters, ISSN 0014-5793, E-ISSN 1873-3468, Vol. 509, no 3, p. 405-412Article in journal (Refereed)
    Abstract [en]

    B-cell leukemia/lymphoma 2 (Bcl-2) blocks oxidant-induced apoptosis at least partly by stabilizing lysosomes. Here we report that phosphorylation of Bcl-2 may be required for these protective effects. J774 cells overexpressing wild-type Bcl-2 resist oxidant-induced lysosomal leak as well as apoptosis, and this protection is amplified by pretreatment with phorbol 12-myristate 13-acetate (which promotes protein kinase C (PKC)-dependent phosphorylation of Bcl-2). In contrast, cells overexpressing the Bcl-2 mutant S70A (which cannot be phosphorylated) are not protected in either circumstance. Transfection with Bcl-2(S70E), a constitutively active Bcl-2 mutant which does not require phosphorylation, is protective independent of PKC activation. In contrast, C2-ceramide, a putative protein phosphatase 2A activator, abolishes the protective effects of wild-type Bcl-2 overexpression but does not diminish protection afforded by Bcl-2(S70E). Additional results suggest that, perhaps as a consequence of lysosomal stabilization, Bcl-2 may prevent activation of phospholipase A2, an event potentially important in the ultimate initiation of apoptosis.

  • 21.
    Zhao, Ming
    et al.
    Linköping University, Department of Neuroscience and Locomotion, Pathology. Linköping University, Faculty of Health Sciences.
    Eaton, John Wallace
    Linköping University, Department of Neuroscience and Locomotion, Pathology. Linköping University, Faculty of Health Sciences.
    Brunk, Ulf
    Linköping University, Department of Neuroscience and Locomotion, Pathology. Linköping University, Faculty of Health Sciences.
    Protection against oxidant-mediated lysosomal rupture: a new anti-apoptotic activity of Bcl-2?2000In: FEBS Letters, ISSN 0014-5793, E-ISSN 1873-3468, Vol. 485, no 2-3, p. 104-108Article in journal (Refereed)
    Abstract [en]

    Bcl-2 antagonizes apoptosis through mechanisms which are not completely understood. We have proposed that apoptosis is initiated by minor lysosomal destabilization followed some time later by secondary massive lysosomal rupture. In J774 cells over-expressing Bcl-2, early oxidant-induced lysosomal destabilization is unaffected but secondary lysosomal rupture and apoptosis are suppressed, despite the fact that wild-type and Bcl-2 over-expressing cells degrade hydrogen peroxide at similar rates. It may be that Bcl-2 directly blocks the effects of released lysosomal enzymes and/or prevents downstream activation of unknown cytosolic pro-enzymes by released lysosomal hydrolases, suggesting a new and heretofore unknown activity of Bcl-2.

  • 22.
    Zhao, Ming
    et al.
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Neuroscience and Locomotion, Pathology.
    Liu, Yawei
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Neuroscience and Locomotion, Pathology.
    Bao, Mingmin
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Biomedicine and Surgery, Cell biology.
    Kato, Yutaka
    Han, Jiahuai
    Eaton, John Wallace
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Neuroscience and Locomotion, Pathology. Östergötlands Läns Landsting, Centre for Laboratory Medicine, Department of Clinical Pathology and Clinical Genetics.
    Vascular smooth muscle cell proliferation requires both p38 and BMK1 MAP kinases2002In: Archives of Biochemistry and Biophysics, ISSN 0003-9861, E-ISSN 1096-0384, Vol. 400, no 2, p. 199-207Article in journal (Refereed)
    Abstract [en]

    Vascular smooth muscle cell (VSMC) proliferation is a key event in the progression of atherosclerosis. Induction of both c-fos (through the transcription factor Elk-1) and c-jun, both immediate early genes, is important for the stimulation of VSMC proliferation and migration. It was earlier found that p38 mitogen-activated protein (MAP) kinase upregulates c-jun gene transcription through phosphorylation of two myocyte enhancer factor 2 (MEF2) family transcription factors, MEF2A and MEF2C, while big MAP kinase 1 (BMK1) may upregulate c-jun gene transcription through MEF2A, MEF2C, and also MEF2D. Here, we report that inhibition of BMK1 by a dominant negative form of MEK5 or pharmacologic inhibition of p38 by SB 203580 additively suppress serum-induced VSMC proliferation. This additive effect of p38 and BMK1 inhibition implies that these two kinases coordinately regulate MEF2 transcription factors. The exclusive activation of MEF2D by BMK1 appears required for this cooperative upregulation of c-jun in VSMC, and coactivation of p38 and BMK1 also has additive effects on the activation of a reporter gene linked to the c-jun promoter in our experimental system. Thus, coordinate activity of both the p38 and BMK1 pathways appears necessary for optimal transcription of c-jun and, pari pasu, VSMC proliferation. These results may have implications for the future design of pharmacologic agents for inhibition of VSMC growth.

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