Search

Your search keyword '"SHANAHAN, C. M."' showing total 112 results
Start Over Author "SHANAHAN, C. M."
112 results on '"SHANAHAN, C. M."'

9. Chronic Kidney Disease and Coronary Artery Disease: JACC State-of-the-Art Review

Author

Sarnak, M. J., Amann, K., Bangalore, S., Cavalcante, J. L., Charytan, D. M., Craig, J. C., Gill, J. S., Hlatky, M. A., Jardine, A. G., Landmesser, U., Newby, L. K., Herzog, C. A., Cheung, M., Wheeler, D. C., Winkelmayer, W. C., Marwick, T. H., Banerjee, D., Briguori, C., Chang, T. I., Chen, C. -L., Defilippi, C. R., Ding, X., Ferro, C. J., Gill, J., Gossl, M., Isbel, N. M., Ishii, H., Jardine, M. J., Kalra, P. A., Laufer, G., Lentine, K. L., Lobdell, K., Lok, C. E., London, G. M., Malyszko, J., Mark, P. B., Marwan, M., Nie, Y., Parfrey, P. S., Pecoits-Filho, R., Pilmore, H., Qunibi, W. Y., Raggi, P., Rattazzi, M., Rossignol, P., Ruturi, J., Sabanayagam, C., Shanahan, C. M., Shroff, G. R., Shroff, R., Webster, A. C., Weiner, D. E., Winther, S., Wiseman, A. C., Yip, A., and Zarbock, A.

Subjects
calcification, acute coronary syndromes, chronic kidney disease, coronary artery disease, revascularization
Published
2019

11. Emerging roles for vascular smooth muscle cell exosomes in calcification and coagulation

Author

Kapustin, A. N. and Shanahan, C. M.

Subjects
Sphingomyelin Phosphodiesterase, Symposium section reviews: Extracellular vesicles, exosomes and microparticles in cardiovascular disease, cardiovascular system, Animals, Humans, Matrix Metalloproteinase 2, musculoskeletal system, Exosomes, Vascular Calcification, Muscle, Smooth, Vascular
Abstract

Vascular smooth muscle cell (VSMC) phenotypic conversion from a contractile to 'synthetic' state contributes to vascular pathologies including restenosis, atherosclerosis and vascular calcification. We have recently found that the secretion of exosomes is a feature of 'synthetic' VSMCs and that exosomes are novel players in vascular repair processes as well as pathological vascular thrombosis and calcification. Pro-inflammatory cytokines and growth factors as well as mineral imbalance stimulate exosome secretion by VSMCs, most likely by the activation of sphingomyelin phosphodiesterase 3 (SMPD3) and cytoskeletal remodelling. Calcium stress induces dramatic changes in VSMC exosome composition and accumulation of phosphatidylserine (PS), annexin A6 and matrix metalloproteinase-2, which converts exosomes into a nidus for calcification. In addition, by presenting PS, VSMC exosomes can also provide the catalytic surface for the activation of coagulation factors. Recent data showing that VSMC exosomes are loaded with proteins and miRNA regulating cell adhesion and migration highlight VSMC exosomes as potentially important communication messengers in vascular repair. Thus, the identification of signalling pathways regulating VSMC exosome secretion, including activation of SMPD3 and cytoskeletal rearrangements, opens up novel avenues for a deeper understanding of vascular remodelling processes.

Published
2016

12. Nesprin-2-dependent ERK1/2 compartmentalisation regulates the DNA damage response in vascular smooth muscle cell ageing

Author

Warren, D. T., Tajsic, T., Porter, L. J., Minaisah, R. M., Cobb, A., Jacob, A., Rajgor, D., Zhang, Q. P., and Shanahan, C. M.

Subjects
Adult, Male, Mitogen-Activated Protein Kinase 1, Original Paper, congenital, hereditary, and neonatal diseases and abnormalities, Mitogen-Activated Protein Kinase 3, DNA Repair, integumentary system, Cell Cycle, Intranuclear Inclusion Bodies, Microfilament Proteins, Nuclear Proteins, Nerve Tissue Proteins, Middle Aged, Lamin Type A, Transfection, Muscle, Smooth, Vascular, Young Adult, Humans, Female, Cellular Senescence, DNA Damage
Abstract

Prelamin A accumulation and persistent DNA damage response (DDR) are hallmarks of vascular smooth muscle cell (VSMC) ageing and dysfunction. Although prelamin A is proposed to interfere with DNA repair, our understanding of the crosstalk between prelamin A and the repair process remains limited. The extracellular signal-regulated kinases 1 and 2 (ERK1/2) have emerged as key players in the DDR and are known to enhance ataxia telangiectasia-mutated protein (ATM) activity at DNA lesions, and in this study, we identified a novel relationship between prelamin A accumulation and ERK1/2 nuclear compartmentalisation during VSMC ageing. We show both prelamin A accumulation and increased DNA damage occur concomitantly, before VSMC replicative senescence, and induce the localisation of ERK1/2 to promyelocytic leukaemia protein nuclear bodies (PML NBs) at the sites of DNA damage via nesprin-2 and lamin A interactions. Importantly, VSMCs treated with DNA damaging agents also displayed prelamin A accumulation and ERK compartmentalisation at PML NBs, suggesting that prelamin A and nesprin-2 are novel components of the DDR. In support of this, disruption of ERK compartmentalisation at PML NBs, by either depletion of nesprin-2 or lamins A/C, resulted in the loss of ATM from DNA lesions. However, ATM signalling and DNA repair remained intact after lamins A/C depletion, whereas nesprin-2 disruption ablated downstream Chk2 activation and induced genomic instability. We conclude that lamins A/C and PML act as scaffolds to organise DNA-repair foci and compartmentalise nesprin-2/ERK signalling. However, nesprin-2/ERK signalling fidelity, but not their compartmentalisation at PML NBs, is essential for efficient DDR in VSMCs.

Published
2015
Full Text
View/download PDF

17. In situ characterization of advanced glycation end products (AGEs) in collagen and model extracellular matrix by solid state NMR.

Author

Li, R., Rajan, R., Wong, W. C. V., Reid, D. G., Duer, M. J., Somovilla, V. J., Martinez-Saez, N., Bernardes, G. J. L., Hayward, R., and Shanahan, C. M.

Subjects
CATIONS, SOLID state chemistry, NUCLEAR magnetic resonance spectroscopy
Abstract

Non-enzymatic glycation of extracellular matrix with (U-13C5)-d-ribose-5-phosphate (R5P), enables in situ 2D ssNMR identification of many deleterious protein modifications and crosslinks, including previously unreported oxalamido and hemiaminal (CH3–CH(OH)NHR) substructures. Changes in charged residue proportions and distribution may be as important as crosslinking in provoking and understanding harmful tissue changes. [ABSTRACT FROM AUTHOR]

Published
2017
Full Text
View/download PDF

24. Poster session 3

Author

Nanka, O., primary, Krejci, E., additional, Pesevski, Z., additional, Sedmera, D., additional, Smart, N., additional, Rossdeutsch, A., additional, Dube, K. N., additional, Riegler, J., additional, Price, A. N., additional, Taylor, A., additional, Muthurangu, V., additional, Turner, M., additional, Lythgoe, M. F., additional, Riley, P. R., additional, Kryvorot, S., additional, Vladimirskaya, T., additional, Shved, I., additional, Schwarzl, M., additional, Seiler, S., additional, Huber, S., additional, Steendijk, P., additional, Maechler, H., additional, Truschnig-Wilders, M., additional, Pieske, B., additional, Post, H., additional, Caprio, C., additional, Baldini, A., additional, Chiavacci, E., additional, Dolfi, L., additional, Verduci, L., additional, Meghini, F., additional, Cremisi, F., additional, Pitto, L., additional, Kuan, T.-C., additional, Chen, M.-C., additional, Yang, T.-H., additional, Wu, W.-T., additional, Lin, C. S., additional, Rai, H., additional, Kumar, S., additional, Sharma, A. K., additional, Mastana, S., additional, Kapoor, A., additional, Pandey, C. M., additional, Agrawal, S., additional, Sinha, N., additional, Orlowska-Baranowska, E. H., additional, Placha, G., additional, Gora, J., additional, Baranowski, R., additional, Abramczuk, E., additional, Hryniewiecki, T., additional, Gaciong, Z., additional, Verschuren, J. J. W., additional, Wessels, J. A. M., additional, Trompet, S., additional, Stott, D. J., additional, Sattar, N., additional, Buckley, B., additional, Guchelaar, H. J., additional, Jukema, J. W., additional, Gharanei, M., additional, Hussain, A., additional, Mee, C. J., additional, Maddock, H. L., additional, Wijnen, W. J., additional, Van Den Oever, S., additional, Van Der Made, I., additional, Hiller, M., additional, Tijsen, A. J., additional, Pinto, Y. M., additional, Creemers, E. E., additional, Nikulina, S. U. Y., additional, Chernova, A., additional, Petry, A., additional, Rzymski, T., additional, Kracun, D., additional, Riess, F., additional, Pike, L., additional, Harris, A. L., additional, Gorlach, A., additional, Katare, R., additional, Oikawa, A., additional, Riu, F., additional, Beltrami, A. P., additional, Cesseli, D., additional, Emanueli, C., additional, Madeddu, P., additional, Zaglia, T., additional, Milan, G., additional, Franzoso, M., additional, Pesce, P., additional, Sarais, C., additional, Sandri, M., additional, Mongillo, M., additional, Butler, T. J., additional, Seymour, A.-M. L., additional, Ashford, D., additional, Jaffre, F., additional, Bussen, M., additional, Flohrschutz, I., additional, Martin, G. R., additional, Engelhardt, S., additional, Kararigas, G., additional, Nguyen, B. T., additional, Jarry, H., additional, Regitz-Zagrosek, V., additional, Van Bilsen, M., additional, Daniels, A., additional, Munts, C., additional, Janssen, B. J. A., additional, Van Der Vusse, G. J., additional, Van Nieuwenhoven, F. A., additional, Montalvo, C., additional, Villar, A. V., additional, Merino, D., additional, Garcia, R., additional, Llano, M., additional, Ares, M., additional, Hurle, M. A., additional, Nistal, J. F., additional, Dembinska-Kiec, A., additional, Beata Kiec-Wilk, B. K. W., additional, Anna Polus, A. P., additional, Urszula Czech, U. C., additional, Tatiana Konovaleva, T. K., additional, Gerd Schmitz, G. S., additional, Bertrand, L., additional, Balteau, M., additional, Timmermans, A., additional, Viollet, B., additional, Sakamoto, K., additional, Feron, O., additional, Horman, S., additional, Vanoverschelde, J. L., additional, Beauloye, C., additional, De Meester, C., additional, Martinez, E., additional, Martin, R., additional, Miana, M., additional, Jurado, R., additional, Gomez-Hurtado, N., additional, Bartolome, M. V., additional, San Roman, J. A., additional, Lahera, V., additional, Nieto, M. L., additional, Cachofeiro, V., additional, Rochais, F., additional, Sturny, R., additional, Mesbah, K., additional, Miquerol, L., additional, Kelly, R. G., additional, Messaoudi, S., additional, Gravez, B., additional, Tarjus, A., additional, Pelloux, V., additional, Samuel, J. L., additional, Delcayre, C., additional, Launay, J. M., additional, Clement, K., additional, Farman, N., additional, Jaisser, F., additional, Hadyanto, L., additional, Castellani, C., additional, Vescovo, G., additional, Ravara, B., additional, Tavano, R., additional, Pozzobon, M., additional, De Coppi, P., additional, Papini, E., additional, Vettor, R., additional, Thiene, G., additional, Angelini, A., additional, Meloni, M., additional, Caporali, A., additional, Cesselli, D., additional, Fortunato, O., additional, Avolio, E., additional, Schindler, R., additional, Simrick, S., additional, Brand, T., additional, Smart, N. S., additional, Herman, A., additional, Roura Ferrer, S., additional, Rodriguez Bago, J., additional, Soler-Botija, C., additional, Pujal, J. M., additional, Galvez-Monton, C., additional, Prat-Vidal, C., additional, Llucia-Valldeperas, A., additional, Blanco, J., additional, Bayes-Genis, A., additional, Foldes, G., additional, Maxime, M., additional, Ali, N. N., additional, Schneider, M. D., additional, Harding, S. E., additional, Reni, C., additional, Mangialardi, G., additional, De Pauw, A., additional, Sekkali, B., additional, Friart, A., additional, Ding, H., additional, Graffeuil, A., additional, Catalucci, D., additional, Balligand, J. L., additional, Azibani, F., additional, Tournoux, F., additional, Schlossarek, S., additional, Polidano, E., additional, Fazal, L., additional, Merval, R., additional, Carrier, L., additional, Chatziantoniou, C., additional, Buyandelger, B., additional, Linke, W., additional, Zou, P., additional, Kostin, S., additional, Ku, C., additional, Felkin, L., additional, Birks, E., additional, Barton, P., additional, Sattler, M., additional, Knoell, R., additional, Schroder, K., additional, Benkhoff, S., additional, Shimokawa, H., additional, Grisk, O., additional, Brandes, R. P., additional, Parepa, I. R., additional, Mazilu, L., additional, Suceveanu, A. I., additional, Suceveanu, A., additional, Rusali, L., additional, Cojocaru, L., additional, Matei, L., additional, Toringhibel, M., additional, Craiu, E., additional, Pires, A. L., additional, Pinho, M., additional, Pinho, S., additional, Sena, C., additional, Seica, R., additional, Leite-Moreira, A., additional, Dabroi, F., additional, Schiaffino, S., additional, Kiseleva, E., additional, Krukov, N., additional, Nikitin, O., additional, Ardatova, L., additional, Mourouzis, I., additional, Pantos, C., additional, Kokkinos, A. D., additional, Cokkinos, D. V., additional, Scoditti, E., additional, Massaro, M., additional, Carluccio, M. A., additional, Pellegrino, M., additional, Calabriso, N., additional, Gastaldelli, A., additional, Storelli, C., additional, De Caterina, R., additional, Lindner, D., additional, Zietsch, C., additional, Schultheiss, H.-P., additional, Tschope, C., additional, Westermann, D., additional, Everaert, B. R., additional, Nijenhuis, V. J., additional, Reith, F. C. M., additional, Hoymans, V. Y., additional, Timmermans, J. P., additional, Vrints, C. J., additional, Simova, I., additional, Mateev, H., additional, Katova, T., additional, Haralanov, L., additional, Dimitrov, N., additional, Mironov, N., additional, Golitsyn, S. P., additional, Sokolov, S. F., additional, Yuricheva, Y. U. A., additional, Maikov, E. B., additional, Shlevkov, N. B., additional, Rosenstraukh, L. V., additional, Chazov, E. I., additional, Radosinska, J., additional, Knezl, V., additional, Benova, T., additional, Slezak, J., additional, Urban, L., additional, Tribulova, N., additional, Virag, L., additional, Kristof, A., additional, Kohajda, Z. S., additional, Szel, T., additional, Husti, Z., additional, Baczko, I., additional, Jost, N., additional, Varro, A., additional, Sarusi, A., additional, Farkas, A. S., additional, Orosz, S. Z., additional, Forster, T., additional, Farkas, A., additional, Zakhrabova-Zwiauer, O. M., additional, Hardziyenka, M., additional, Nieuwland, R., additional, Tan, H. L., additional, Raaijmakers, A. J. A., additional, Bourgonje, V. J. A., additional, Kok, G. J. M., additional, Van Veen, A. A. B., additional, Anderson, M. E., additional, Vos, M. A., additional, Bierhuizen, M. F. A., additional, Benes, J., additional, Sebestova, B., additional, Ghouri, I. A., additional, Kemi, O. J., additional, Kelly, A., additional, Burton, F. L., additional, Smith, G. L., additional, Ozdemir, S., additional, Acsai, K., additional, Doisne, N., additional, Van Der Nagel, R., additional, Beekman, H. D. M., additional, Van Veen, T. A. B., additional, Sipido, K. R., additional, Antoons, G., additional, Harmer, S. C., additional, Mohal, J. S., additional, Kemp, D., additional, Tinker, A., additional, Beech, D., additional, Burley, D. S., additional, Cox, C. D., additional, Wann, K. T., additional, Baxter, G. F., additional, Wilders, R., additional, Verkerk, A., additional, Fragkiadaki, P., additional, Germanakis, G., additional, Tsarouchas, K., additional, Tsitsimpikou, C., additional, Tsardi, M., additional, George, D., additional, Tsatsakis, A., additional, Rodrigues, P., additional, Barros, C., additional, Najmi, A. K., additional, Khan, V., additional, Akhtar, M., additional, Pillai, K. K., additional, Mujeeb, M., additional, Aqil, M., additional, Bayliss, C. R., additional, Messer, A. E., additional, Leung, M.-C., additional, Ward, D., additional, Van Der Velden, J., additional, Poggesi, C., additional, Redwood, C. S., additional, Marston, S., additional, Vite, A., additional, Gandjbakhch, E., additional, Gary, F., additional, Fressart, V., additional, Leprince, P., additional, Fontaine, G., additional, Komajda, M., additional, Charron, P., additional, Villard, E., additional, Falcao-Pires, I., additional, Gavina, C., additional, Hamdani, N., additional, Stienen, G. J. M., additional, Niessens, H. W. M., additional, Leite-Moreira, A. F., additional, Paulus, W. J., additional, Memo, M., additional, Marston, S. B., additional, Vafiadaki, E., additional, Qian, J., additional, Arvanitis, D. A., additional, Sanoudou, D., additional, Kranias, E. G., additional, Elmstedt, N., additional, Lind, B., additional, Ferm-Widlund, K., additional, Westgren, M., additional, Brodin, L.-A., additional, Mansfield, C., additional, West, T., additional, Ferenczi, M., additional, Wijnker, P. J. M., additional, Foster, D. B., additional, Coulter, A., additional, Frazier, A., additional, Murphy, A. M., additional, Shah, M., additional, Sikkel, M. B., additional, Desplantez, T., additional, Collins, T. P., additional, O' Gara, P., additional, Lyon, A. R., additional, Macleod, K. T., additional, Ottesen, A. H., additional, Louch, W. E., additional, Carlson, C., additional, Landsverk, O. J. B., additional, Stridsberg, M., additional, Sjaastad, I., additional, Oie, E., additional, Omland, T., additional, Christensen, G., additional, Rosjo, H., additional, Cartledge, J., additional, Clark, L. A., additional, Ibrahim, M., additional, Siedlecka, U., additional, Navaratnarajah, M., additional, Yacoub, M. H., additional, Camelliti, P., additional, Terracciano, C. M., additional, Chester, A., additional, Gonzalez-Tendero, A., additional, Torre, I., additional, Garcia-Garcia, F., additional, Dopazo, J., additional, Gratacos, E., additional, Taylor, D., additional, Bhandari, S., additional, Seymour, A.-M., additional, Fliegner, D., additional, Jost, J., additional, Bugger, H., additional, Ventura-Clapier, R., additional, Carpi, A., additional, Campesan, M., additional, Canton, M., additional, Menabo, R., additional, Pelicci, P. G., additional, Giorgio, M., additional, Di Lisa, F., additional, Hancock, M., additional, Venturini, A., additional, Al-Shanti, N., additional, Stewart, C., additional, Ascione, R., additional, Angelini, G., additional, Suleiman, M.-S., additional, Kravchuk, E., additional, Grineva, E., additional, Galagudza, M., additional, Kostareva, A., additional, Bairamov, A., additional, Krychtiuk, K. A., additional, Watzke, L., additional, Kaun, C., additional, Demyanets, S., additional, Pisoni, J., additional, Kastl, S. P., additional, Huber, K., additional, Maurer, G., additional, Wojta, J., additional, Speidl, W. S., additional, Varga, Z. V., additional, Farago, N., additional, Zvara, A., additional, Kocsis, G. F., additional, Pipicz, M., additional, Csonka, C., additional, Csont, T., additional, Puskas, G. L., additional, Ferdinandy, P., additional, Klevstigova, M., additional, Silhavy, J., additional, Manakov, D., additional, Papousek, F., additional, Novotny, J., additional, Pravenec, M., additional, Kolar, F., additional, Novakova, O., additional, Novak, F., additional, Neckar, J., additional, Barallobre-Barreiro, J., additional, Didangelos, A., additional, Yin, X., additional, Fernandez-Caggiano, M., additional, Drozdov, I., additional, Willeit, P., additional, Domenech, N., additional, Mayr, M., additional, Lemoine, S., additional, Allouche, S., additional, Coulbault, L., additional, Galera, P., additional, Gerard, J. L., additional, Hanouz, J. L., additional, Suveren, E., additional, Whiteman, M., additional, Studneva, I. M., additional, Pisarenko, O., additional, Shulzhenko, V., additional, Serebryakova, L., additional, Tskitishvili, O., additional, Timoshin, A., additional, Fauconnier, J., additional, Meli, A. C., additional, Thireau, J., additional, Roberge, S., additional, Lompre, A. M., additional, Jacotot, E., additional, Marks, A. M., additional, Lacampagne, A., additional, Dietel, B., additional, Altendorf, R., additional, Daniel, W. G., additional, Kollmar, R., additional, Garlichs, C. D., additional, Parente, V., additional, Balasso, S., additional, Pompilio, G., additional, Colombo, G., additional, Milano, G., additional, Squadroni, L., additional, Cotelli, F., additional, Pozzoli, O., additional, Capogrossi, M. C., additional, Ajiro, Y., additional, Saegusa, N., additional, Iwade, K., additional, Giles, W. R., additional, Stafforini, D. M., additional, Spitzer, K. W., additional, Sirohi, R., additional, Candilio, L., additional, Babu, G., additional, Roberts, N., additional, Lawrence, D., additional, Sheikh, A., additional, Kolvekar, S., additional, Yap, J., additional, Hausenloy, D. J., additional, Yellon, D. M., additional, Aslam, M., additional, Rohrbach, S., additional, Schlueter, K.-D., additional, Piper, H. M., additional, Noll, T., additional, Guenduez, D., additional, Malinova, L., additional, Ryabukho, V. P., additional, Lyakin, D. V., additional, Denisova, T. P., additional, Montoro-Garcia, S., additional, Shantsila, E., additional, Lip, G. Y. H., additional, Kalaska, B., additional, Sokolowska, E., additional, Kaminski, K., additional, Szczubialka, K., additional, Kramkowski, K., additional, Mogielnicki, A., additional, Nowakowska, M., additional, Buczko, W., additional, Stancheva, N., additional, Mekenyan, E., additional, Gospodinov, K., additional, Tisheva, S., additional, Darago, A., additional, Rutkai, I., additional, Kalasz, J., additional, Czikora, A., additional, Orosz, P., additional, Bjornson, H. D., additional, Edes, I., additional, Papp, Z., additional, Toth, A., additional, Riches, K., additional, Warburton, P., additional, O'regan, D. J., additional, Ball, S. G., additional, Turner, N. A., additional, Wood, I. C., additional, Porter, K. E., additional, Kogaki, S., additional, Ishida, H., additional, Nawa, N., additional, Takahashi, K., additional, Baden, H., additional, Ichimori, H., additional, Uchikawa, T., additional, Mihara, S., additional, Miura, K., additional, Ozono, K., additional, Lugano, R., additional, Padro, T., additional, Garcia-Arguinzonis, M., additional, Badimon, L., additional, Ferraro, F., additional, Viner, R., additional, Ho, J., additional, Cutler, D., additional, Matchkov, V., additional, Aalkjaer, C., additional, Krijnen, P. A. J., additional, Hahn, N. E., additional, Kholova, I., additional, Sipkens, J. A., additional, Van Alphen, F. P., additional, Simsek, S., additional, Schalkwijk, C. G., additional, Van Buul, J. D., additional, Van Hinsbergh, V. W. M., additional, Niessen, H. W. M., additional, Caro, C. G., additional, Seneviratne, A., additional, Monaco, C., additional, Hou, D., additional, Singh, J., additional, Gilson, P., additional, Burke, M. G., additional, Heraty, K. B., additional, Krams, R., additional, Coppola, G., additional, Albrecht, K., additional, Schgoer, W., additional, Wiedemann, D., additional, Bonaros, N., additional, Steger, C., additional, Theurl, M., additional, Stanzl, U., additional, Kirchmair, R., additional, Amadesi, S., additional, Spinetti, G., additional, Cangiano, E., additional, Valgimigli, M., additional, Miller, A. M., additional, Cardinali, A., additional, Vierlinger, K., additional, Pagano, G., additional, Liccardo, D., additional, Zincarelli, C., additional, Femminella, G. D., additional, Lymperopoulos, A., additional, De Lucia, C., additional, Koch, W. J., additional, Leosco, D., additional, Rengo, G., additional, Hinkel, R., additional, Husada, W., additional, Trenkwalder, T., additional, Di, Q., additional, Lee, S., additional, Petersen, B., additional, Bock-Marquette, I., additional, Niemann, H., additional, Di Maio, M., additional, Kupatt, C., additional, Nourian, M., additional, Yassin, Z., additional, Kelishadi, R., additional, Memarian, S. H., additional, Heidari, A., additional, Leuner, A., additional, Poitz, D. M., additional, Brunssen, C., additional, Ravens, U., additional, Strasser, R. H., additional, Morawietz, H., additional, Vogt, F., additional, Grahl, A., additional, Flege, C., additional, Marx, N., additional, Borinski, M., additional, De Geest, B., additional, Jacobs, F., additional, Muthuramu, I., additional, Gordts, S. C., additional, Van Craeyveld, E., additional, Herijgers, P., additional, Weinert, S., additional, Medunjanin, S., additional, Herold, J., additional, Schmeisser, A., additional, Braun-Dullaeus, R. C., additional, Wagner, A. H., additional, Moeller, K., additional, Adolph, O., additional, Schwarz, M., additional, Schwale, C., additional, Bruehl, C., additional, Nobiling, R., additional, Wieland, T., additional, Schneider, S. W., additional, Hecker, M., additional, Cross, A., additional, Strom, A., additional, Cole, J., additional, Goddard, M., additional, Hultgardh-Nilsson, A., additional, Nilsson, J., additional, Mauri, C., additional, Mitkovskaya, N. P., additional, Kurak, T. A., additional, Oganova, E. G., additional, Shkrebneva, E. I., additional, Kot, Z. H. N., additional, Statkevich, T. V., additional, Molica, F., additional, Burger, F., additional, Matter, C. M., additional, Thomas, A., additional, Staub, C., additional, Zimmer, A., additional, Cravatt, B., additional, Pacher, P., additional, Steffens, S., additional, Blanco, R., additional, Sarmiento, R., additional, Parisi, C., additional, Fandino, S., additional, Blanco, F., additional, Gigena, G., additional, Szarfer, J., additional, Rodriguez, A., additional, Garcia Escudero, A., additional, Riccitelli, M. A., additional, Wantha, S., additional, Simsekyilmaz, S., additional, Megens, R. T., additional, Van Zandvoort, M. A., additional, Liehn, E., additional, Zernecke, A., additional, Klee, D., additional, Weber, C., additional, Soehnlein, O., additional, Lima, L. M., additional, Carvalho, M. G., additional, Gomes, K. B., additional, Santos, I. R., additional, Sousa, M. O., additional, Morais, C. A. S., additional, Oliveira, S. H. V., additional, Gomes, I. F., additional, Brandao, F. C., additional, Lamego, M. R. A., additional, Fornai, L., additional, Kiss, A., additional, Giskes, F., additional, Eijkel, G., additional, Fedrigo, M., additional, Valente, M. L., additional, Heeren, R. M. A., additional, Grdinic, A., additional, Vojvodic, D., additional, Djukanovic, N., additional, Grdinic, A. G., additional, Obradovic, S., additional, Majstorovic, I., additional, Rusovic, S., additional, Vucinic, Z., additional, Tavciovski, D., additional, Ostojic, M., additional, Lai, S.-C., additional, Chen, M.-Y., additional, Wu, H.-T., additional, Gouweleeuw, L., additional, Oberdorf-Maass, S. U., additional, De Boer, R. A., additional, Van Gilst, W. H., additional, Maass, A. H., additional, Van Gelder, I. C., additional, Benard, L., additional, Li, C., additional, Warren, D., additional, Shanahan, C. M., additional, Zhang, Q. P., additional, Bye, A., additional, Vettukattil, R., additional, Aspenes, S. T., additional, Giskeodegaard, G., additional, Gribbestad, I. S., additional, Wisloff, U., additional, Bathen, T. F., additional, Cubedo, J., additional, Alonso, R., additional, Mata, P., additional, Ivic, I., additional, Vamos, Z., additional, Cseplo, P., additional, Kosa, D., additional, Torok, O., additional, Hamar, J., additional, Koller, A., additional, Norita, K., additional, De Noronha, S. V., additional, Sheppard, M. N., additional, Amat-Roldan, I., additional, Iruretagoiena, I., additional, Psilodimitrakopoulos, S., additional, Crispi, F., additional, Artigas, D., additional, Loza-Alvarez, P., additional, Harrison, J. C., additional, Smart, S. D., additional, Besely, E. H., additional, Kelly, J. R., additional, Yao, Y., additional, Sammut, I. A., additional, Hoepfner, M., additional, Kuzyniak, W., additional, Sekhosana, E., additional, Hoffmann, B., additional, Litwinski, C., additional, Pries, A., additional, Ermilov, E., additional, Fontoura, D., additional, Lourenco, A. P., additional, Vasques-Novoa, F., additional, Pinto, J. P., additional, Roncon-Albuquerque, R., additional, Oyeyipo, I. P., additional, Olatunji, L. A., additional, Usman, T. O., additional, Olatunji, V. A., additional, Bacova, B., additional, Viczenczova, C., additional, Dosenko, V., additional, Goncalvesova, E., additional, Vanrooyen, J., additional, Maulik, S. K., additional, Seth, S., additional, Dinda, A. K., additional, Jaiswal, A., additional, Mearini, G., additional, Khajetoorians, D., additional, Kraemer, E., additional, Gedicke-Hornung, C., additional, Precigout, G., additional, Eschenhagen, T., additional, Voit, T., additional, Garcia, L., additional, Lorain, S., additional, Mendes-Ferreira, P., additional, Maia-Rocha, C., additional, Adao, R., additional, Cerqueira, R. J., additional, Mendes, M. J., additional, Castro-Chaves, P., additional, De Keulenaer, G. W., additional, Bras-Silva, C., additional, Ruiter, G., additional, Wong, Y. Y., additional, Lubberink, M., additional, Knaapen, P., additional, Raijmakers, P., additional, Lammertsma, A. A., additional, Marcus, J. T., additional, Westerhof, N., additional, Van Der Laarse, W. J., additional, Vonk-Noordegraaf, A., additional, Steinbronn, N., additional, Koch, E., additional, Steiner, G., additional, Berezin, A., additional, Lisovaya, O. A., additional, Soldatova, A. M., additional, Kuznetcov, V. A., additional, Yenina, T. N., additional, Rychkov, A. Y. U., additional, Shebeko, P. V., additional, Altara, R., additional, Hessel, M. H. M., additional, Hermans, J. J. R., additional, Blankesteijn, W. M., additional, Berezina, T. A., additional, Seden, V., additional, Bonanad, C., additional, Nunez, J., additional, Navarro, D., additional, Chilet, M. F., additional, Sanchis, F., additional, Bodi, V., additional, Minana, G., additional, Chaustre, F., additional, Forteza, M. J., additional, Llacer, A., additional, Galasso, G., additional, Ferrara, N., additional, Akhmedov, A., additional, Klingenberg, R., additional, Brokopp, C., additional, Hof, D., additional, Zoller, S., additional, Corti, R., additional, Gay, S., additional, Von Eckardstein, A., additional, Hoerstrup, S. P., additional, Luescher, T. F., additional, Heijman, J., additional, Zaza, A., additional, Johnson, D. M., additional, Rudy, Y., additional, Peeters, R. L. M., additional, Volders, P. G. A., additional, Westra, R. L., additional, Fujita, S., additional, Okamoto, R., additional, Taniguchi, M., additional, Konishi, K., additional, Goto, I., additional, Sugimoto, K., additional, Nakamura, M., additional, Shiraki, K., additional, Buechler, C., additional, and Ito, M., additional

Published
2012
Full Text
View/download PDF

34. Mechanisms of vascular calcification in renal disease.

Author

Shanahan, C. M.

Subjects
CALCIFICATION, CALCIUM in the body, UREMIA, KIDNEY diseases, ALPHA fetoproteins, BLOOD proteins
Abstract

Vascular calcification is common place in patients with end-stage renal disease where it develops rapidly and predicts a variety of adverse outcomes. The processes responsible for vascular calcification have been the focus of much re search, aided in recent decades by molecular genetic techniques and in vitro models. Converging evidence now suggests that vascular calcification is an active, regulated process, with abundant similarities to the process of skeletal mineralization. Using an in vitro model of calcifying vascular smooth muscle cells (VSMCs), we have shown that a mineral imbalance induces VSMC apoptosis, and that VSMC apoptotic bodies and vesicles can nucleate basic calcium phosphate in the form of hydroxyapatite, the same mineral found in bone. Gene expression studies suggest that the normal vessel wall expresses proteins such as matrix Gla protein that inhibit calcification. In addition, circulating proteins such as fetuin-A are produced at remote sites and act to inhibit soft tissue calcification systemically. However, down-regulation or perturbation of these proteins may lead to a phenotypic transformation of VSMCs to osteo/chondrocytic-like cells while the calcified environment may stimulate macrophages to adopt osteoclastic properties. Both clinical and basic research findings indicate an inverse relation ship between bone mineralization and vascular calcification. The mechanisms linking these two processes are a topic for further investigation, with current theories proposing a role for lipids, common regulatory molecules, and calcium and bone turn over. We have synthesized these findings into a theoretical model offering a putative pathway for the development of severe vascular calcification in endstage renal disease. [ABSTRACT FROM AUTHOR]

Published
2005
Full Text
View/download PDF

37. Role for alkaline phosphatase as an inducer of vascular calcification in renal failure?

Author

Schoppet, M. and Shanahan, C. M.

Subjects
*PHOSPHATASES, *ALKALINE phosphatase, *CALCIFICATION, *KIDNEY diseases, *HYDROLYSIS, *HYDROXYAPATITE
Abstract

Vascular calcification is associated with increased cardiovascular morbidity and mortality. A number of calcification inhibitors have been defined recently, including inorganic pyrophosphate (PPi), an important physicochemical inhibitor of hydroxyapatite crystal growth. Increased hydrolysis of PPi by tissue-nonspecific alkaline phosphatase (TNAP) may occur in renal failure and act to enhance mineralization of vessels.Kidney International (2008) 73, 989–991. doi:10.1038/ki.2008.104 [ABSTRACT FROM AUTHOR]

Published
2008
Full Text
View/download PDF

39. Regulation of expression of a sheep metallothionein 1a-sheep growth hormone fusion gene in transgenic mice

Author

Shanahan, C M, Rigby, N W, Murray, J D, Marshall, J T, Townrow, C A, Nancarrow, C D, and Ward, K A

Abstract

Transgenic mice containing a sheep metallothionein 1a-sheep growth hormone fusion gene exhibited low, tissue-specific basal levels of transgene mRNA expression, resulting in slightly elevated levels of circulating growth hormone that did not lead to a detectable increase in growth. After zinc stimulation, high levels of transgene mRNA expression were induced in a number of tissues; these levels correlated with increased levels of circulating growth hormone, resulting in growth increases of up to 1.5 times the levels of controls and unstimulated transgenic mice. After removal of the zinc stimulus, transgene expression and circulating growth hormone concentrations returned to basal levels. Additional evidence from the pattern of developmental expression of the transgene suggests that zinc is the main regulator of this promoter in mice. The demonstrated regulation and low basal level of expression of the sheep metallothionein 1a promoter make it a candidate for use in other mouse transgenic studies and for use in transgenic livestock, in which regulation of expression is essential.

Published
1989
Full Text
View/download PDF

41. Prelamin A accelerates vascular calcification via activation of the DNA damage response and senescence associated secretory phenotype in vascular smooth muscle cells.

Author

Liu, Y., Drozdov, I., Shroff, R., Beltran, L. E., and Shanahan, C. M.

Subjects
VASCULAR diseases, DNA damage, CYTOKINES
Abstract

Vascular calcification is prevalent in the ageing population yet little is known of the mechanisms driving age-associated vascular smooth muscle cell (VSMC) phenotypic change. Recent evidence has implicated nuclear lamina dysfunction, especially the accumulation of premature forms of lamin A, in promoting premature cellular ageing, as typified in the premature ageing disorder Hutchison-Gilford Progeria Syndrome.[1, 2] Our previous data showed that Prelamin A, the unprocessed form of the nuclear lamina protein lamin A, accumulates in aged and atherosclerotic arteries and, acts as a specific hallmark of VSMC ageing, within the general population.[3] In the current study we investigated whether prelamin A accumulation plays a role in driving VSMC osteogenic differentiation. We found that prelamin A accumulated in cacifying VSMCs both in vitro and in vivo and that overexpression of prelamin A in vitro promoted VSMC osteogenic differentiation and mineralization. During VSMC ageing in vitro prelamin A accumulation occurred concomitantly with increased p16 expression and osteogenic differentiation and was associated with increased levels of DNA damage. Microarray analysis showed that DNA damage repair pathways were significantly impaired in VSMCs expressing prelamin A and chemical inhibition or siRNA depletion of the DNA damage response (DDR) kinases ATM/ATR effectively blocked VSMC osteogenic differentiation and mineralization. In co-culture experiments, prelamin A expressing VSMCs induced alkaline phosphatase (ALP) activity in mesenchymal progenitor cells and this was abrogated by inhibition of ATM signalling suggesting DNA damage induces the secretion of pro-osteogenic factors by VSMCs. Cytokine array analysis identified a number of ATM-dependent senescence associated secretory phenotype (SASP) factors/cytokines released by prelamin A positive VSMCs including the calcification regulators BMP2, OPG and IL6, and these data were validated by quantitative PCR and ELISA. This study demonstrates that prelamin A promotes premature VSMC calcification and ageing, in part, by inducing persistent DNA damage signalling which acts upstream of VSMC osteogenic differentiation and the SASP. Agents that target the DDR and/or prelamin A toxicity may be potential therapies for the treatment of vascular calcification. [ABSTRACT FROM AUTHOR]

Published
2013

42. Mineral imbalance and loss of contractile phenotype induce vascular smooth muscle cell calcification by promoting exosome secretion.

Author

Kapustin, A. N., Drozdov, I., Soong, D., Furmanik, M., Alvarez-Hernandez, D., Sanchis, P., Molls, R., Shroff, R., Yin, X., Skepper, J., Mayr, M., and Shanahan, C. M.

Subjects
MUSCLE cells, CYTOKINES, SMOOTH muscle
Abstract

Vascular calcification is a tightly-regulated pathological process that is triggered by multiple factors ranging from extracellular mineral imbalance to pro-inflammatory cytokines and orchestrated by the osteogenic phenotypic transition of vascular smooth muscle cells (VSMCs). VSMCs secrete matrix vesicles (MVs), loaded with the calcification inhibitor fetuin-A, into the extracellular matrix and these serve as a nidus for calcification. Here we studied the mechanisms of MV secretion by VSMCs. Fetuin-A is internalized by VSMCs and delivered to late endosomes/multivesicular bodies and secreted in MVs via the exosomal pathway. Biochemical analysis showed that MVs originate from multivesicular bodies and are enriched with exosomal markers including CD9, CD63 and Tsg101. Proteomic analysis showed that VSMC exosomes partially share proteomic composition with exosomes secreted by other cells and are enriched with proteins involved in the regulation of cell adhesion and migration. Furthermore, fetuin-A secretion and VSMC MV secretion were blocked by GW4869, an inhibitor of sphingomyelin phosphodiesterase 3 (SMPD3) which regulates exosome biogenesis. Treatment of VSMCs in the presence of elevated extracellular calcium resulted in a significant increase in exosome secretion and this was associated with the upregulation of SMPD3 expression. Inhibition of SMPD3 prevented VSMC calcification indicating that exosome secretion is required for the initiation of VSMC calcification. Next we examined how the phenotypic transition influences exosome secretion and VSMC calcification. Heparin and TGF-β treatment markedly reduced VSMC proliferation and induced expression of VSMC contractile markers, calponin and α-smooth muscle actin. In contrast, treatment with the pro-inflammatory cytokine TNF-α induced VSMC proliferation accompanied by a reduction in contractile phenotype markers. Comparing exosome secretion revealed a significant increase in exosome secretion in the presence of TNF-α and reduced exosome production by the heparin or TGF-β treated VSMCs. Finally, in agreement with our in vitro data, EM analysis of longitudinal sections of VSMCs in human vessel rings ex vivo revealed MVB-like structures in VSMCs. Immunohistochemical staining of normal and atherosclerotic human aortic and carotid artery samples showed no presence of exosomal marker CD63 in the normal vessel wall. However, extensive CD63 staining was observed in the atherosclerotic vasculature particularly in association with calcified VSMCs. In conclusion, we found that fetuin-A is recycled via exosomal pathway and VSMC exosome secretion is regulated by SMPD3. Modulation of exosome secretion by mineral imbalance and phenotypic transition as well as loading with fetuin-A are novel regulatory pathways for VSMC calcification. [ABSTRACT FROM AUTHOR]

Published
2013

43. The role of ER stress in vascular calcification.

Author

Furmanik, M. and Shanahan, C. M.

Subjects
*HYDROXYAPATITE, *BLOOD vessels, *HYPERTROPHY
Abstract

Vascular calcification is a pathological process of deposition of calcium and phosphate crystals in the form of hydroxyapatite (HAp) in the blood vessel wall. Its presence in the vessel wall causes stiffness and leads to left ventricular hypertrophy and increases cardiovascular morbidity and mortality. It is a serious health problem common in ageing populations and widely prevalent in pathological conditions such as diabetes and chronic kidney disease. Vascular calcification is a regulated, cell-mediated process, similar to bone formation that involves osteogenic transdifferention of vascular smooth muscle cells (VSMCs) characterized by expression of bone-specific genes in the calcified vessel. However, the exact mechanisms responsible for triggering this process are unknown. The endoplasmic reticulum (ER) is involved in the production, correct folding and secretion of newly synthesized proteins in cells. ER stress occurs as a result of unfolded protein accumulation or an increased demand for protein secretion. It results in activation of a signalling pathway called the unfolded protein response (UPR), mediated by three main ER stress transducers IRE1, PERK and ATF6. Importantly, ER stress has recently been implicated in bone development. Therefore, we hypothesized that phenotypic conversion and calcification of VSMCs can be regulated by ER stress. Human primary VSMCs were treated with tunicamycin and thapsigargin and expression of bone markers in response to ER stress was examined by Western blotting and quantitative real-time PCR. ER stress was shown to regulate expression of BMP2, a key bone morphogen and Osterix, an obligate bone specific transcription factor, as well as its downstream targets bone sialoprotein, alkaline phosphatase and osteoprotegerin in VSMCs. However no effects on Runx2 were observed. In addition, the two different ER stress inducers were found to have differential effects on activation of these bone markers. Using siRNA knock-down it was established that two branches of the UPR represented by ATF6 and ATF4 (downstream of PERK) play a role in mediating these effects on bone gene expression. Further analysis of Osterix, the osteogenic transcription factor shown to be regulated by ER stress, demonstrated that it localised predominantly in cytoplasmic foci and was present in matrix vesicles secreted by VSMCs suggesting it may play a novel role in mediating the VSMC response to ER stress. [ABSTRACT FROM AUTHOR]

Published
2013

44. Vascular smooth muscle cell-derived exosomes isolated from human blood are enriched with fetuin-A, and may be involved in the mechanisms of vascular calcification.

Author

Kalra, S. S., Kapustin, A., Abbas, A., Smith, A., Waltham, M., and Shanahan, C. M.

Subjects
BONE growth, CALCIFICATION, BIOMINERALIZATION
Abstract

Vascular calcification (VC) is a highly regulated process with many similarities to developmental osteogenesis. Key features include release of vascular smooth muscle cell (VSMC) derived exosomes and dysregulated expression of physiological inhibitors of calcification such as fetuin-A (1). In vitro, fetuin-A is internalised by VSMCs and loaded into these exosomes which is thought to be a physiological mechanism to inhibit calcification. However this process becomes overwhelmed by calcification-inducing stress resulting in the loss of fetuin-A from the exosomes, thereby rendering them mineralisation competent to form the nidus for calcification (2). In dialysis-dependent patients with chronic renal disease, lower levels of serum fetuin-A are associated with VC (3) and fetuin-A co-localises with calcified arteries (2) suggesting that a similar inhibitory mechanism exists as seen in vitro. However it is unknown if an exosome-fetuin mechanism exists in the general, non-renal failure, population. Determine if fetuin-A enriched VSMC exosomes are found in the human circulation and if they reflect calcification stress. Exosomes isolated from human whole blood by differential centrifugation were enriched with the exosomal marker CD63 and contained the VSMC-specific marker α-smooth muscle actin, as detected by Western Blot. Using Western blot, fetuin-A was also detected in VSMC exosomes isolated from patients with and without clinically confirmed VC, with an observation of lower levels of fetuin-A in subjects with VC. In a cohort (n=16) of patients with VC, we investigated the relationship between exosomal fetuin-A (as determined by ELISA), exosomal calcium (as determined by a cresolphthalein assay) and clinically quantified VC (computed tomography derived calcium score). Linear regression analysis showed a negative correlation between the exosomal fetuin-A:calcium ratio and calcium score [r2 = -0.65; p<0.05] (see figure 1). VSMC-derived exosomes are present in the human circulation and contain the calcification inhibitor fetuin-A. A negative correlation exists between VSMC exosomal fetuin-A and clinical calcification, confirming previous in vitro observations that fetuin-A enriched VSMC exosomes may inhibit VC and could serve as a clinical marker of VC in the general population. [ABSTRACT FROM AUTHOR]

Published
2013

46. Exploring the biology of vascular calcification in chronic kidney disease: What's circulating?

Author

Schoppet, M., Shroff, R. C., Hofbauer, L. C., and Shanahan, C. M.

Subjects
*CALCIFICATION, *CHRONIC kidney failure, *KIDNEY diseases, *CALCIUM in the body, *PRESERVATION of organs, tissues, etc., *BIOMINERALIZATION
Abstract

Chronic kidney disease (CKD) is associated with fatal cardiovascular consequences in part due to ectopic calcification of soft tissues particularly arteries, capillaries, and cardiac valves. An increasing body of evidence from experimental studies and in vivo data suggest that (I) a mineral imbalance with hyperphosphatemia and high-circulating calcium × phosphate product, (II) a deficiency of systemic or local calcification inhibitors, (III) death or ‘damage’ of vascular smooth muscle cells (VSMCs), and/or (IV) phenotypic transformation of VSMCs to osteo/chondrocytic cells may all act in concert to initiate and sustain vascular calcification. In CKD patients inhibitory systems are overwhelmed by a multitude of agents that induce VSMC damage and cell death resulting in the release of vesicles capable of nucleating basic calcium phosphate. Studies with genetically altered mice have identified both local and systemic calcification inhibitors that act to maintain VSMC differentiation or regulate vesicle properties. However, for many of these proteins the mechanisms and sites of action are still under investigation. In particular, it is unclear whether factors present in the circulation have an inhibitory role there and whether circulating levels of these proteins influence or are indicative of underlying disease processes in individual patients. A greater understanding of the origins and roles of potential circulating inhibitors may result in novel strategies aimed at the prevention or reversal of the life-limiting calcifying vasculopathies seen in CKD patients.Kidney International (2008) 73, 384–390; doi:10.1038/sj.ki.5002696; published online 28 November 2007 [ABSTRACT FROM AUTHOR]

Published
2008
Full Text
View/download PDF

47. Nesprins: a novel family of spectrin-repeat-containing proteins that localize to the nuclear membrane in multiple tissues.

Author

Zhang Q, Skepper JN, Yang F, Davies JD, Hegyi L, Roberts RG, Weissberg PL, Ellis JA, and Shanahan CM

Subjects
Amino Acid Sequence, Animals, Biomarkers, COS Cells, Cell Differentiation genetics, Cells, Cultured, Cytoskeletal Proteins, DNA, Complementary isolation & purification, Humans, Immune Sera chemistry, In Situ Hybridization, Fluorescence, Membrane Proteins chemistry, Membrane Proteins genetics, Membrane Proteins immunology, Mice, Microfilament Proteins, Molecular Sequence Data, Multigene Family, Muscle Proteins chemistry, Muscle Proteins genetics, Muscle, Smooth, Vascular cytology, Muscle, Smooth, Vascular metabolism, Nuclear Localization Signals genetics, Nuclear Proteins chemistry, Nuclear Proteins genetics, Nuclear Proteins immunology, Organ Specificity genetics, Protein Structure, Tertiary genetics, Rats, Repetitive Sequences, Amino Acid, Sequence Homology, Amino Acid, Subcellular Fractions metabolism, Membrane Proteins metabolism, Muscle Proteins metabolism, Nerve Tissue Proteins, Nuclear Envelope metabolism, Nuclear Proteins metabolism, Spectrin metabolism
Abstract

In search of vascular smooth muscle cell differentiation markers, we identified two genes encoding members of a new family of type II integral membrane proteins. Both are ubiquitously expressed, and tissue-specific alternative mRNA initiation and splicing generate at least two major isoforms of each protein, with the smaller isoforms being truncated at the N-terminus. We have named these proteins nesprin-1 and -2 for nuclear envelope spectrin repeat, as they are characterized by the presence of multiple, clustered spectrin repeats, bipartite nuclear localization sequences and a conserved C-terminal, single transmembrane domain. Transient transfection of EGFP-fusion expression constructs demonstrated their localization to the nuclear membrane with a novel C-terminal, TM-domain-containing sequence essential for perinuclear localization. Using antibodies to nesprin-1, we documented its colocalization with LAP1, emerin and lamins at the nuclear envelope, and immunogold labeling confirmed its presence at the nuclear envelope and in the nucleus where it colocalized with heterochromatin. Nesprin-1 is developmentally regulated in both smooth and skeletal muscle and is re-localized from the nuclear envelope to the nucleus and cytoplasm during C2C12 myoblast differentiation. These data and structural analogies with other proteins suggest that nesprins may function as 'dystrophins of the nucleus' to maintain nuclear organization and structural integrity.

Published
2001
Full Text
View/download PDF

48. A polymorphism of the human matrix gamma-carboxyglutamic acid protein promoter alters binding of an activating protein-1 complex and is associated with altered transcription and serum levels.

Author

Farzaneh-Far A, Davies JD, Braam LA, Spronk HM, Proudfoot D, Chan SW, O'Shaughnessy KM, Weissberg PL, Vermeer C, and Shanahan CM

Subjects
Animals, Aorta, Binding Sites, Calcium-Binding Proteins chemistry, Cell Nucleus metabolism, Cells, Cultured, Chondrocytes metabolism, Extracellular Matrix Proteins chemistry, Extracellular Matrix Proteins metabolism, Humans, Muscle, Smooth, Vascular metabolism, Polymorphism, Single-Stranded Conformational, Rats, Rats, Wistar, Recombinant Fusion Proteins metabolism, Recombinant Proteins chemistry, Recombinant Proteins metabolism, Tetradecanoylphorbol Acetate pharmacology, Transcription Factor AP-1 chemistry, Transfection, Matrix Gla Protein, Calcium-Binding Proteins genetics, Calcium-Binding Proteins metabolism, Extracellular Matrix Proteins genetics, Gene Expression Regulation, Polymorphism, Genetic, Promoter Regions, Genetic, Transcription Factor AP-1 metabolism, Transcription, Genetic
Abstract

Matrix gamma-carboxyglutamic acid protein (MGP) is a mineral-binding extracellular matrix protein synthesized by vascular smooth muscle cells (VSMCs) and chondrocytes that is thought to be a key regulator of tissue calcification. In this study, we identified four polymorphisms in the promoter region of the human MGP gene. Transfection studies showed that the G-7A and T-138C polymorphisms have an important impact on in vitro promoter activity when transiently transfected into VSMCs. We found that one of these polymorphisms (T-138C) is significantly correlated with serum MGP levels in human subjects. Promoter deletion analysis showed that this polymorphism lies in a region of the promoter critical for transcription in VSMCs. This region contains a potential activating protein-1 (AP-1) binding element located between -142 and -136. We have demonstrated that the T-138C polymorphism results in altered binding of an AP-1 complex to this region. The -138T allelic variant binds AP-1 complexes consisting primarily of c-Jun, JunB and its partners Fra-1 and Fra-2 in rat VSMC. Furthermore, the -138T variant form of the promoter was induced following phorbol 12-myristate 13-acetate treatment, while the -138C variant was refractive to phorbol 12-myristate 13-acetate treatment, confirming that AP-1 factors preferentially bind to the -138T variant. This study therefore suggests that a common polymorphism of the MGP promoter influences binding of the AP-1 complex, which may lead to altered transcription and serum levels. This could have important implications for diseases such as atherosclerosis and aortic valve stenosis, since it strongly suggests a genetic basis for regulation of tissue calcification.

Published
2001
Full Text
View/download PDF

49. Biology of calcification in vascular cells: intima versus media.

Author

Proudfoot D and Shanahan CM

Subjects
Adult, Age Factors, Aged, Animals, Apoptosis, Arteriosclerosis etiology, Arteriosclerosis physiopathology, Calcinosis etiology, Calcinosis genetics, Calcinosis physiopathology, Cells, Cultured, Coronary Artery Disease etiology, Coronary Artery Disease pathology, Coronary Artery Disease physiopathology, Diabetic Neuropathies etiology, Diabetic Neuropathies pathology, Elastin metabolism, Elastin physiology, Gene Expression, Humans, Lipid Metabolism, Mice, Mice, Knockout, Muscle, Smooth, Vascular metabolism, Muscle, Smooth, Vascular pathology, Phenotype, Risk Factors, Arteriosclerosis pathology, Calcinosis pathology, Endothelium, Vascular pathology, Tunica Intima pathology
Abstract

Background: Vascular calcification occurs at two distinct sites within the vessel wall: the intima and the media. Intimal calcification occurs in the context of atherosclerosis, associated with lipid, macrophages and vascular smooth muscle cells, whereas medial calcification can exist independently of atherosclerosis and is associated with elastin and vascular smooth muscle cells., Pathogenesis: In this review we compare intimal and medial calcification, particularly discussing the mechanisms which may be responsible for each type of calcification. Similar mechanisms probably initiate and regulate both forms of calcification including the generation of matrix vesicles/apoptotic bodies and local expression of mineralization-regulating proteins. However, since different modifying agents such as lipids in the intima and elastin in the media are present at the sites of calcification and are associated with particular diseases, this implies that the etiologies of these processes differ. For example, intimal calcification is associated with atherosclerosis while medial calcification occurs commonly in the diabetic neuropathic leg., Clinical Importance: Since both types of calcification correlate with significant morbidity and mortality, we discuss the different types of calcification in terms of their clinical importance.

Published
2001
Full Text
View/download PDF

50. Transcriptional regulation of matrix gla protein.

Author

Farzaneh-Far A, Weissberg PL, Proudfoot D, and Shanahan CM

Subjects
Animals, Cholecalciferol pharmacology, Cyclic AMP pharmacology, Down-Regulation drug effects, Gene Expression Regulation drug effects, Humans, Muscle, Smooth, Vascular drug effects, Rats, Transforming Growth Factor beta pharmacology, Tretinoin pharmacology, Up-Regulation drug effects, Matrix Gla Protein, Arteriosclerosis genetics, Calcinosis genetics, Calcium-Binding Proteins genetics, Extracellular Matrix Proteins, Transcription, Genetic genetics
Abstract

Matrix Gla Protein (MGP) is a small protein which is thought to be an inhibitor of tissue calcification and a regulator of cell differentiation. In this study we have examined the transcriptional regulation of MGP within rat vascular smooth muscle cells (VSMCs). We found that MGP transcription is downregulated by retinoic acid and transforming growth factor beta (TGF beta) whereas it is upregulated by vitamin D3 and cyclic AMP.

Published
2001
Full Text
View/download PDF

Catalog

Books, media, physical & digital resources
See catalog results