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3. Vaccine targeting ANGPTL3 ameliorates dyslipidemia and associated diseases in mouse models of obese dyslipidemia and familial hypercholesterolemia

Author

Fukami, H, primary, Morinaga, J, additional, Nakagami, H, additional, Hayashi, H, additional, Okadome, Y, additional, Matsunaga, E, additional, Kadomatsu, T, additional, Horiguchi, H, additional, Sato, M, additional, Sugizaki, T, additional, Kuwabara, T, additional, Miyata, K, additional, Mukoyama, M, additional, Morishita, R, additional, and Oike, Y, additional

Published
2022
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5. SWITCH 1/DYAD is a WINGS APART-LIKE antagonist that maintains sister chromatid cohesion in meiosis

Author

Yang, C., Hamamura, Y., Sofroni, K., Böwer, F., Stolze, S., Nakagami, H., and Schnittger, A.

Subjects
0301 basic medicine, Science, Arabidopsis, General Physics and Astronomy, Cell Cycle Proteins, 02 engineering and technology, Chromatids, Biology, Article, General Biochemistry, Genetics and Molecular Biology, Evolution, Molecular, 03 medical and health sciences, Prophase, Meiosis, Homologous chromosome, Sister chromatids, lcsh:Science, Anaphase, Multidisciplinary, Cohesin, Arabidopsis Proteins, Nuclear Proteins, General Chemistry, 021001 nanoscience & nanotechnology, Cell biology, Establishment of sister chromatid cohesion, 030104 developmental biology, lcsh:Q, Separase, 0210 nano-technology
Abstract

Mitosis and meiosis both rely on cohesin, which embraces the sister chromatids and plays a crucial role for the faithful distribution of chromosomes to daughter cells. Prior to the cleavage by Separase at anaphase onset, cohesin is largely removed from chromosomes by the non-proteolytic action of WINGS APART-LIKE (WAPL), a mechanism referred to as the prophase pathway. To prevent the premature loss of sister chromatid cohesion, WAPL is inhibited in early mitosis by Sororin. However, Sororin homologs have only been found to function as WAPL inhibitors during mitosis in vertebrates and Drosophila. Here we show that SWITCH 1/DYAD defines a WAPL antagonist that acts in meiosis of Arabidopsis. Crucially, SWI1 becomes dispensable for sister chromatid cohesion in the absence of WAPL. Despite the lack of any sequence similarities, we found that SWI1 is regulated and functions in a similar manner as Sororin hence likely representing a case of convergent molecular evolution across the eukaryotic kingdom., During cell division, Soronin antagonises WAPL to prevent premature loss of sister chromatid cohesion. Here the authors show that, despite a lack of sequence similarity, the Arabidopsis SWI1 protein functions as a novel Soronin-like WAPL antagonist, suggesting convergent evolution with animals.

Published
2019

8. Current status of the multinational Arabidopsis community

Author

Parry, Geraint, Provart, Nicholas J., Brady, Siobhan M., Uzilday, Baris, Adams, K., Araújo, W., Aubourg, S., Baginsky, S., Bakker, E., Bärenfaller, K., Batley, J., Beale, M., Beilstein, M., Belkhadir, Y., Berardini, T., Bergelson, J., Blanco-Herrera, F., Brady, S., Braun, Hans-Peter, Briggs, S., Brownfield, L., Cardarelli, M., Castellanos-Uribe, M., Coruzzi, G., Dassanayake, M., Jaeger, G.D., Dilkes, B., Doherty, C., Ecker, J., Edger, P., Edwards, D., Kasmi, F.E., Eriksson, M., Exposito-Alonso, M., Falter-Braun, P., Fernie, A., Ferro, M., Fiehn, O., Friesner, J., Greenham, K., Guo, Y., Hamann, T., Hancock, A., Hauser, M.-T., Heazlewood, J., Ho, C.-H., Hõrak, H., Huala, E., Hwang, I., Iuchi, S., Jaiswal, P., Jakobson, L., Jiang, Y., Jiao, Y., Jones, A., Kadota, Y., Khurana, J., Kliebenstein, D., Knee, E., Kobayashi, M., Koch, M., Krouk, G., Larson, T., Last, R., Lepiniec, L., Li, S., Lurin, C., Lysak, M., Maere, S., Malinowski, R., Maumus, F., May, S., Mayer, K., Mendoza-Cozatl, D., Mendoza-Poudereux, I., Meyers, B., Micol, J.L., Millar, H., Mock, H.-P., Mukhtar, K., Mukhtar, S., Murcha, M., Nakagami, H., Nakamura, Y., Nicolov, L., Nikolau, B., Nowack, M., Nunes-Nesi, A., Palmgren, M., Parry, G., Patron, N., Peck, S., Pedmale, U., Perrot-Rechenmann, C., Pieruschka, R., Pío-Beltrán, J., Pires, J.C., Provart, N., Rajjou, L., Reiser, L., Reumann, S., Rhee, S., Rigas, S., Rolland, N., Romanowski, A., Santoni, V., Savaldi-Goldstein, S., Schmitz, R., Schulze, W., Seki, M., Shimizu, K.K., Slotkin, K., Small, I., Somers, D., Sozzani, R., Spillane, C., Srinivasan, R., Taylor, N., Tello-Ruiz, M.-K., Thelen, J., Tohge, T., Town, C., Toyoda, T., Uzilday, B., Peer, Y.V.D., Wijk, K., Gillhaussen, P.V., Walley, J., Ware, D., Weckwerth, W., Whitelegge, J., Wienkoop, S., Wright, C., Wrzaczek, M., Yamazaki, M., Yanovsky, M., Žárský, V., Zhong, X., Biological Systems Engineering, Organisms and Environment Research Division, Cardiff School of Biosciences, Cardiff University, University of Toronto, University of California [Davis] (UC Davis), University of California, Institut de Recherche en Horticulture et Semences (IRHS), Université d'Angers (UA)-AGROCAMPUS OUEST, Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro)-Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Institute of Biochemistry and Biotechnology, Martin Luther University Halle-Wittenberg, 06099 Halle, Germany, Department of Ecology and Evolution [Chicago], University of Chicago, Biochimie et Physiologie Moléculaire des Plantes (BPMP), Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS)-Institut national d’études supérieures agronomiques de Montpellier (Montpellier SupAgro), Unité de recherche en génomique végétale (URGV), Institut National de la Recherche Agronomique (INRA)-Université d'Évry-Val-d'Essonne (UEVE)-Centre National de la Recherche Scientifique (CNRS), Eidgenössische Technische Hochschule - Swiss Federal Institute of Technology [Zürich] (ETH Zürich), Rothamsted Research, Biotechnology and Biological Sciences Research Council (BBSRC), University of Arizona, Gregor Mendel Institute (GMI) - Vienna Biocenter (VBC), Austrian Academy of Sciences (OeAW), University of California (UC), Center for Genomics and Systems Biology, Department of Biology [New York], New York University [New York] (NYU), NYU System (NYU)-NYU System (NYU)-New York University [New York] (NYU), NYU System (NYU)-NYU System (NYU), Flanders Institute for Biotechnology, National Center for Atmospheric Research [Boulder] (NCAR), Max Planck Institute of Molecular Plant Physiology (MPI-MP), Max-Planck-Gesellschaft, Laboratoire de Biologie à Grande Échelle (BGE - UMR S1038), Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Grenoble Alpes (UGA), Agricultural Sustainability Institute and Department of Neurobiology, Physiology, and Behavior, Norwegian University of Science and Technology (NTNU), University of Melbourne, King Abdullah University of Science and Technology (KAUST), University of Chinese Academy of Sciences [Beijing] (UCAS), The Sainsbury Laboratory [Norwich] (TSL), IBM Research – Tokyo, University Medical Center Groningen [Groningen] (UMCG), Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS)-Institut national d’études supérieures agronomiques de Montpellier (Montpellier SupAgro)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Centre for Novel Agricultural Products, Department of Biology, University of York [York, UK], Biologie des Semences (LBS), Institut National de la Recherche Agronomique (INRA)-Institut National Agronomique Paris-Grignon (INA P-G), Sichuan University [Chengdu] (SCU), Institut des Sciences des Plantes de Paris-Saclay (IPS2 (UMR_9213 / UMR_1403)), Université d'Évry-Val-d'Essonne (UEVE)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Department of Plant Systems Biology, Unité de Recherche Génomique Info (URGI), Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), University of Nottingham, UK (UON), Institute of Bioinformatics and System Biology (IBIS), Helmholtz Zentrum München = German Research Center for Environmental Health, Saint Mary's University [Halifax], Max Planck Institute for Plant Breeding Research (MPIPZ), National Institute of Genetics (NIG), University of Copenhagen = Københavns Universitet (UCPH), Division of Biology [La Jolla], University of California [San Diego] (UC San Diego), University of California (UC)-University of California (UC), Earlham Institute [Norwich], Forschungszentrum Jülich GmbH | Centre de recherche de Juliers, Helmholtz-Gemeinschaft = Helmholtz Association, University of Missouri [Columbia] (Mizzou), University of Missouri System, Institut Jean-Pierre Bourgin (IJPB), AgroParisTech-Université Paris-Saclay-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Department of Plant Biology, Carnegie Institution for Science, Dynamique du protéome et biogenèse du chloroplaste (ChloroGenesis), Physiologie cellulaire et végétale (LPCV), Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Université Grenoble Alpes (UGA)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Université Grenoble Alpes (UGA), Plateforme de Spectrométrie de Masse Protéomique - Mass Spectrometry Proteomics Platform (MSPP), Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Plant Systems Biology, Institute of Physiology and Biotechnology of plants, RIKEN Center for Sustainable Resource Science [Yokohama] (RIKEN CSRS), RIKEN - Institute of Physical and Chemical Research [Japon] (RIKEN), Unité de recherche Génétique et amélioration des plantes (GAP), Institut National de la Recherche Agronomique (INRA), Department of Biology, Duke University, Genetics and Biotechnology Lab, Plant & AgriBiosciences Research Centre (PABC), School of Natural Sciences, National University of Ireland [Galway] (NUI Galway), Universidade Federal de São Paulo, RIKEN Plant Science Center and RIKEN Bioinformatics and Systems Engineering Division, Cold Spring Harbor Laboratory (CSHL), University of Vienna [Vienna], University of California [Los Angeles] (UCLA), Department of Plant Molecular Biology, Université de Lausanne = University of Lausanne (UNIL), UKRI-BBSRC grant BB/M004376/1, HHMI Faculty Scholar Fellowship, Turkiye Bilimsel ve Teknolojik Arastirma Kurumu (TUBITAK) 118Z137, UK Research & Innovation (UKRI) Biotechnology and Biological Sciences Research Council (BBSRC) BB/M004376/1, Sainsbury Lab, Norwich Research Park, Université d'Évry-Val-d'Essonne (UEVE)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Helmholtz-Zentrum München (HZM), University of Copenhagen = Københavns Universitet (KU), University of California-University of California, Carnegie Institution for Science [Washington], Université de Lausanne (UNIL), Ege Üniversitesi, Organismal and Evolutionary Biology Research Programme, Plant Biology, Viikki Plant Science Centre (ViPS), Receptor-Ligand Signaling Group, University of Zurich, Parry, Geraint, Provart, Nicholas J, and Brady, Siobhan M

Subjects
0106 biological sciences, Arabidopsis thaliana, [SDV]Life Sciences [q-bio], White Paper, Genetics and Molecular Biology (miscellaneous), Plant Science, Biochemistry, 01 natural sciences, Dewey Decimal Classification::500 | Naturwissenschaften::580 | Pflanzen (Botanik), Research community, Arabidopsis, 1110 Plant Science, 0303 health sciences, Ecology, biology, 1184 Genetics, developmental biology, physiology, ddc:580, Multinational corporation, MAP, 590 Animals (Zoology), Life Sciences & Biomedicine, Arabidopsis research community, Evolution, Steering committee, Multinational Arabidopsis Steering Committee, Library science, 1301 Biochemistry, Genetics and Molecular Biology (miscellaneous), Biochemistry, Genetics and Molecular Biology (miscellaneous), Business and Economics, 10127 Institute of Evolutionary Biology and Environmental Studies, 03 medical and health sciences, Behavior and Systematics, Political science, [SDV.BV]Life Sciences [q-bio]/Vegetal Biology, MASC, roadmap, Ecology, Evolution, Behavior and Systematics, 030304 developmental biology, [SDV.GEN]Life Sciences [q-bio]/Genetics, Plant Sciences, Botany, 15. Life on land, 11831 Plant biology, biology.organism_classification, White Papers, collaboration, 1105 Ecology, Evolution, Behavior and Systematics, QK1-989, Arabidopsis Thaliana, Collaboration, Research Network, Roadmap, 570 Life sciences, 1182 Biochemistry, cell and molecular biology, 2303 Ecology, 010606 plant biology & botany
Abstract

The multinational Arabidopsis research community is highly collaborative and over the past thirty years these activities have been documented by the Multinational Arabidopsis Steering Committee (MASC). Here, we (a) highlight recent research advances made with the reference plantArabidopsis thaliana; (b) provide summaries from recent reports submitted by MASC subcommittees, projects and resources associated with MASC and from MASC country representatives; and (c) initiate a call for ideas and foci for the "fourth decadal roadmap," which will advise and coordinate the global activities of the Arabidopsis research community., UKRI-BBSRC grant [BB/M004376/1]; HHMI Faculty Scholar Fellowship; Scientific and Technological Research Council of TurkeyTurkiye Bilimsel ve Teknolojik Arastirma Kurumu (TUBITAK) [118Z137], UKRI-BBSRC grant, Grant/Award Number: BB/M004376/1; HHMI Faculty Scholar Fellowship; the Scientific and Technological Research Council of Turkey, Grant/Award Number: 118Z137

Published
2020

14. DEVELOPMENT OF THERAPEUTIC VACCINE FOR GERIATRIC MEDICINE

Author

Nakagami, H, Yoshida, S, Nakajima, T, Takeda, S, and Rakugi, H

Subjects
Abstracts
Abstract

Recent research on vaccination has extended its scope from infectious diseases to chronic diseases, and we have reported that angiotensin II vaccine for hypertension or DPP4 vaccine for diabetes successfully attenuated the high blood pressure with its complications or hyperglycemia in each mice model, respectively (PLoS One 2013, PNAS 2014, Stroke 2017, Sci Rep 2017). Here, we proposed a novel concept of our therapeutic vaccine for aging-related diseases. First target of our approach is S100A9 (S100 calcium-binding protein A9), one of alarmins released from platelet or macrophage as a trigger of inflammation. S100A9 vaccine successfully induced anti-S100A9 antibody without cytotoxic reaction. Since S100A9/CD36 signaling contributes thrombus formation, the immunized mice were exposed to vascular injury for thrombosis formation. The occlusion time was significantly delayed in the mice immunized with S100A9 vaccine, which was comparable to that in the mice treated with 6 mg/kg clopidogrel. In the evaluation of coagulation system, there was no significant difference in tail bleeding time between S100A9-vaccinated mice and the control mice, whereas tail bleeding time in the mice treated with clopidogrel was significantly longer. Second approach of our strategy is to deplete the aging-cells by therapeutic vaccine which mimic senolysis therapy. We successfully developed the vaccine for aging T-cells. Under high fat diet, administration of the vaccine decreased the numbers of aging T-cells in white adipose tissue and the immunized mice improved systemic glucose intolerance in mice. These novel immunotherapies may contribute the preventive medicine to control the chronic inflammation with aging.

Published
2018

15. The GYF domain protein PSIG1 dampens the induction of cell death during plant-pathogen interactions

Author

Matsui, H., Nomura, Y., Egusa, M., Hamada, T., Hyon, G., Kaminaka, H., Watanabe, Y., Ueda, T., Trujillo, M., Shirasu, K., and Nakagami, H.

Subjects
Leaves, lcsh:QH426-470, Arabidopsis Thaliana, Arabidopsis, Plant Pathogens, Plant Science, Brassica, Research and Analysis Methods, Necrotic Cell Death, Model Organisms, Protein Domains, Gene Expression Regulation, Plant, Plant and Algal Models, Genetics, Plant Diseases, Staining, Cell Death, Arabidopsis Proteins, Plant Anatomy, Organisms, Biology and Life Sciences, Cell Staining, Eukaryota, Cell Biology, Plants, Plant Pathology, Nonsense Mediated mRNA Decay, Phenotypes, lcsh:Genetics, Experimental Organism Systems, Cell Processes, Specimen Preparation and Treatment, Seedlings, Host-Pathogen Interactions, Carrier Proteins, Reactive Oxygen Species, Salicylic Acid, Research Article
Abstract

The induction of rapid cell death is an effective strategy for plants to restrict biotrophic and hemi-biotrophic pathogens at the infection site. However, activation of cell death comes at a high cost, as dead cells will no longer be available for defense responses nor general metabolic processes. In addition, necrotrophic pathogens that thrive on dead tissue, take advantage of cell death-triggering mechanisms. Mechanisms by which plants solve this conundrum remain described. Here, we identify PLANT SMY2-TYPE ILE-GYF DOMAIN-CONTAINING PROTEIN 1 (PSIG1) and show that PSIG1 helps to restrict cell death induction during pathogen infection. Inactivation of PSIG1 does not result in spontaneous lesions, and enhanced cell death in psig1 mutants is independent of salicylic acid (SA) biosynthesis or reactive oxygen species (ROS) production. Moreover, PSIG1 interacts with SMG7, which plays a role in nonsense-mediated RNA decay (NMD), and the smg7-4 mutant allele mimics the cell death phenotype of the psig1 mutants. Intriguingly, the psig1 mutants display enhanced susceptibility to the hemi-biotrophic bacterial pathogen. These findings point to the existence and importance of the SA- and ROS-independent cell death constraining mechanism as a part of the plant immune system., Author summary Programmed cell death (PCD) has crucial roles in development and immunity in multicellular organisms. In plants, rapid PCD induction, so-called hypersensitive response (HR) cell death, can be triggered as a part of immune system, and plays an important role in restricting pathogen growth. Despite its importance, cell death induction can backfire on plants because of the diversified infection strategies of plant pathogens. It is therefore assumed that plants have mechanisms by which they are able to minimize PCD induction during plant-pathogen interactions. However, their existence and biological significance are not clear yet. Here, we demonstrate that PSIG1, which has the GYF domain that is highly conserved among diverse eukaryotic species, restricts cell death induction during pathogen invasions. Importantly, psig1 mutants do not display autoimmune phenotypes, and are more susceptible to the virulent bacterial pathogen. Our findings suggest that the restriction of cell death can have benefits for plants to defend themselves against hemi-biotrophic bacterial pathogen infections. We further provide evidence suggesting a mechanism by which PSIG1 may contain cell death by regulating the RNA metabolism machinery.

Published
2017

18. TDM1 Regulation Determines the Number of Meiotic Divisions

Author

Ma, H, Cifuentes, M, Jolivet, S, Cromer, L, Harashima, H, Bulankova, P, Renne, C, Crismani, W, Nomura, Y, Nakagami, H, Sugimoto, K, Schnittger, A, Riha, K, Mercier, R, Ma, H, Cifuentes, M, Jolivet, S, Cromer, L, Harashima, H, Bulankova, P, Renne, C, Crismani, W, Nomura, Y, Nakagami, H, Sugimoto, K, Schnittger, A, Riha, K, and Mercier, R

Abstract

Cell cycle control must be modified at meiosis to allow two divisions to follow a single round of DNA replication, resulting in ploidy reduction. The mechanisms that ensure meiosis termination at the end of the second and not at the end of first division are poorly understood. We show here that Arabidopsis thaliana TDM1, which has been previously shown to be essential for meiotic termination, interacts directly with the Anaphase-Promoting Complex. Further, mutations in TDM1 in a conserved putative Cyclin-Dependant Kinase (CDK) phosphorylation site (T16-P17) dominantly provoked premature meiosis termination after the first division, and the production of diploid spores and gametes. The CDKA;1-CYCA1.2/TAM complex, which is required to prevent premature meiotic exit, phosphorylated TDM1 at T16 in vitro. Finally, while CYCA1;2/TAM was previously shown to be expressed only at meiosis I, TDM1 is present throughout meiosis. These data, together with epistasis analysis, lead us to propose that TDM1 is an APC/C component whose function is to ensure meiosis termination at the end of meiosis II, and whose activity is inhibited at meiosis I by CDKA;1-TAM-mediated phosphorylation to prevent premature meiotic exit. This provides a molecular mechanism for the differential decision of performing an additional round of division, or not, at the end of meiosis I and II, respectively.

Published
2016

20. The Biphasic Effects of Oxidized-Low Density Lipoprotein on the Vasculogenic Function of Endothelial Progenitor Cells

Author

Lin, FY, Tsao, NW, Shih, CM, Lin, YW, Yeh, JS, Chen, JW, Nakagami, H, Morishita, R, Sawamura, T, and Huang, CY

Subjects
embryonic structures, cardiovascular system, lipids (amino acids, peptides, and proteins), circulatory and respiratory physiology
Abstract

Late-outgrowth endothelial progenitor cells (EPCs) are stress-resistant and responsible for reparative functions in the cardiovascular system. Oxidized-LDL (oxLDL) plays a critical role in cardiovascular disease pathogenesis. However, it is largely unknown what the impacts of oxLDL are on late-outgrowth EPCs. This study aimed to investigate the concentration-related effects of oxLDL on EPC functions and related angiogenesis, in vitro and in vivo. In this study, early and late-outgrowth EPCs were generated from circulating human mononuclear cells. oxLDL may regulate EPC vasculogenic function via the lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1). Lower concentrations (5 μg/mL) of oxLDL can potentiate EPC tube formation in vitro and in vivo by activating eNOS mechanisms, which are mediated by p38 MAPK- and SAPK/JNK-related pathways. Higher concentrations of oxLDL (10-50 μg/mL) impaired EPC function via the activation of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase pathways and consequent inhibition of eNOS activity, which could be reversed by anti-oxidants (diphenylene iodonium and apocynin) and gp91phox siRNA. In conclusion, oxLDL has concentration-dependent biphasic effects on human late-outgrowth EPC tube formation in vitro and in vivo., Article, PLOS ONE.10(5):e0123971(2015)

Published
2015

45. Phosphorylation of p38 mitogen-activated protein kinase downstream of bax-caspase-3 pathway leads to cell death induced by high D-glucose in human endothelial cells.

Author

Nakagami, Hironori, Morishita, Ryuichi, Yamamoto, Kei, Yoshimura, Shin-ichi, Taniyama, Yoshiaki, Aoki, Motokuni, Matsubara, Hiroaki, Kim, Shokei, Kaneda, Yasufumi, Ogihara, Toshio, Nakagami, H, Morishita, R, Yamamoto, K, Yoshimura, S I, Taniyama, Y, Aoki, M, Matsubara, H, Kim, S, Kaneda, Y, and Ogihara, T

Subjects
APOPTOSIS, PROTEIN kinases, GLUCOSE
Abstract

Because high D-glucose significantly stimulates endothelial cell death, we examined the molecular mechanisms of high D-glucose-induced endothelial apoptosis. Treatment of human aortic endothelial cells with high D-glucose (25 mmol/l), but not mannitol and L-glucose, resulted in a significant decrease in cell number and a significant increase in apoptotic cells as compared with a physiological concentration (5 mmol/l). Interestingly, high D-glucose treatment significantly increased bax protein, accompanied by translocation of bax protein from cytosol to mitochondria-enriched heavy membrane fraction. In contrast, the expression and distribution of bcl-2 protein were not altered by high D-glucose. In addition, the activity of caspase-3 proteases was increased after exposure to high glucose, whereas caspase inhibitors prevented endothelial cell death induced by high D-glucose. On the other hand, p38 mitogen-activated protein kinase (MAPK) was markedly phosphorylated and showed sustained phosphorylation after stimulation. A specific inhibitor of p38 MAPK, SB 203580, and the overexpression of kinase-inactive p38 MAPK significantly attenuated cell death induced by high D-glucose in human aortic endothelial cells, whereas at 6 h after high D-glucose treatment, SB 203580 and overexpression of kinase-inactive p38 MAPK did not attenuate caspase-3 activation induced by high D-glucose. Importantly, caspase inhibitors significantly attenuated the sustained phosphorylation of p38 MAPK induced by high D-glucose. Thus, we finally focused the MAPK kinase (MEK) kinase 1 (MEKK1) to further examine the cross-talk between p38 MAPK and the bax-caspase proteases pathway. High D-glucose treatment induced MEKK1 cleavage, whereas caspase inhibitors significantly attenuated the cleavage. Importantly, kinase-inactive MEKK1 also blocked the phosphorylation of p38 MAPK induced by high D-glucose. Here, we demonstrated that high D-glucose induced apoptosis in human endothelial cells through activation of the bax-caspase proteases pathway and through phosphorylation of p38 MAPK mediated by MEKK1. Phosphorylation of p38 MAPK downstream of the bax-caspase pathway may play a pivotal role in endothelial apoptosis mediated by high D-glucose. [ABSTRACT FROM AUTHOR]

Published
2001
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