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9. Sciences within European Young Researcher Community272The neuro-cardiac interaction defines an extracellular microdomain required for neurotrophic signaling273Gut microbiota is important in the development of angiotensin II driven arterial hypertension and vascular dysfunction in mice274Role of the mitochondrial protein Opa1 in the regulation of the cardiac sympathetic neuron physiology

Author

Franzoso, M, primary, Karbach, S, primary, Prando, V, primary, Zaglia, T, additional, Pianca, N, additional, Vitiello, L, additional, Mongillo, M, additional, Hoermann, NH, additional, Jaeckel, SJ, additional, Schoenfelder, TS, additional, Schueler, RS, additional, Finger, SF, additional, Kossmann, SK, additional, Knorr, MK, additional, Brandt, MB, additional, Wilms, EW, additional, Waisman, AW, additional, Muenzel, TM, additional, Baekhed, FB, additional, Reinhardt, CR, additional, Wenzel, PW, additional, Incensi, A, additional, Franzoso, M, additional, Donadio, V, additional, and Scorrano, L, additional

Published
2016
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11. Moderated Poster Session - Heart245The involvement of TWEAK and FN14 in murine autoimmune myocarditis246Sympathetic neurons that innervate the heart locally modulate cardiomyocyte trophic and electrophysiological properties247W4R variant of CSRP3 leads to the expression of a novel alternate reading frame protein due to alternative splicing248Glucocorticoid intervention prenatally: effects on fetal heart maturation249Uncoupling of myofilament Ca2+-sensitivity from troponin I phosphorylation by hypertrophic and dilated cardiomyopathy mutations can be reversed by EGCG and related Hsp90 inhibitors250Investigating inherited HCM caused by SCO2 and PRKAG2 mutations using the patients' induced pluripotent stem cell-derived cardiomyocytes

Author

Fischer, A, primary, Pianca, N, primary, Azzimato, V, primary, Batchen, E J, primary, Messer, A E, primary, Ben Jehuda, R, primary, Mueller, A-M, additional, Bangert, A, additional, Bockstahler, M, additional, Oettl, R, additional, Katus, HA, additional, Kaya, Z, additional, Prando, V, additional, Franzoso, M, additional, Di Bona, A, additional, Campione, M, additional, Sandri, M, additional, Zaglia, T, additional, Mongillo, M, additional, Tabish, AM, additional, Buyandelger, B, additional, Enesa, KN, additional, Hunt, J, additional, Milner, R, additional, Wiseman, JW, additional, Wahlgren, J, additional, Bohlooly, M, additional, Knoell, R, additional, Richardson, R V, additional, Thomson, A J W, additional, Moran, C M, additional, Gray, G A, additional, Chapman, K E, additional, Papadaki, M, additional, Vikhorev, PG, additional, Sheehan, A, additional, Marston, SB, additional, Hallas, T, additional, Haykain, T, additional, Eisen, B, additional, Schick, R, additional, Gherghiceanu, M, additional, Mandel, H, additional, Arad, M, additional, and Binah, O, additional

Published
2016
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12. 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. 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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. 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Published
2012
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13. P94 The neuro-cardiac interaction defines an extracellular microdomain required for neurotrophic signaling.

Author

Franzoso, M, Zaglia, T, Pianca, N, Di Benedetto, G, Sandre, M, Gobbo, V, Schiaffino, S, Marin, O, Lo Preiato, R, and Mongillo, M

Subjects
*NEUROTROPHIC functions, *CELLULAR signal transduction, *NEURONS, *BRAIN physiology, *MYOCARDIUM, *HEART rate monitoring
Abstract

Purpose: Sympathetic ganglia neurons (SGNs) innervate the myocardium and tune heart rate and contractility. Development and viability of cardiac neurons depend on neurotrophins that are released in low amounts by the myocardium. This study aims to understand whether the direct cell-to-cell contact plays a role in NGF-mediated signaling between cardiomyocytes (CMs) and SGNs.Methods and results: Electron microscopy and immunofluorescence on mouse heart slices and rat SGN/CM co-cultures showed a close association between SGNs and CMs, neurotransmitter vesicle accumulation, increased membrane protein density and enrichment of the NGF receptor (TrkA) at the contact site. These data support that specialized and locally organized signaling domains exist (neuro-cardiac junction, NCJ, hereafter).We tested the functional role of the NCJ in NGF-mediated prosurvival signaling. NGF expression by CMs was assessed by western blot analysis and its silencing in co-cultures caused a 66% decrease of neuronal density, suggesting that neurons depend on NGF released by CMs. NGF binding to its receptor triggers TrkA retrograde transport to neuronal soma that was monitored using fluorescently labeled TrkA. TrkA-RFP retrograde movements were faster in processes contacting CMs than other cardiac cells, further supporting that neuronal NGF signaling is activated by the coupled CMs. SGNs cultured on NGF-silenced CMs showed a 20% decrease in the NCJ area when compared to those on wild type CMs of the same culture. Moreover, NGF uptake was observed only in processes contacting NGF overexpressing CMs, supporting that neurotrophin mediated signaling is involved at the SGN/CM interaction. Consistently, cultured SGNs in contact with CMs survived NGF withdrawal, whereas neurons alone treated with CM-conditioned medium did not survive because of the very low NGF concentration (<5pg/mL).An anti-NGF antibody, a TrkA antagonist (c(92-96)) and inhibitor (k252a) were used to antagonize receptor activation by NGF. Only the small membrane permeable k252a reduced neuronal density, suggesting that the NCJ is an isolated microdomain. K252a was used to estimate NGF concentration at the contact site, which resulted about 1.5nM, four orders of magnitude higher than that in CM-conditioned medium, supporting that the NCJ allows amplification of intercellular NGF signaling.Conclusions: Taken together, our results suggest that the NGF-dependent pro-survival signal to the SGN needs a direct interaction with the CM that facilitates NGF activation of TrkA thanks to the development of an isolated microdomain characterized by a high NGF concentration. [ABSTRACT FROM AUTHOR]

Published
2014
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14. P607 Cardiac sympathetic innervation determines regional heterogeneity in morphology and function of cardiomyocytes.

Author

Pianca, N, Zaglia, T, Nalotto, L, Franzoso, M, Brum, P, Sandri, M, and Mongillo, M

Subjects
HEART cells, CELL morphology, SYMPATHETIC nervous system, CELL physiology, PROTEOLYSIS, CELLULAR signal transduction
Abstract

Purpose: Cardiac Sympathetic Neurons (cSNs) densely innervate the myocardium and operate physiologically both as short term enhancers of cardiac function, and as constitutive regulator of cardiomyocyte (CM) size, by controlling proteolysis through the β2-AR/FOXO3/MuRF-1 dependent signaling axis (1). The density of cSNs decreases progressively from the epi- to the endocardium. We here tested the hypothesis that such innervation pattern would reflect on the degree of constitutive β2-AR input to the different regions of the heart and thus heterogenously control myocardial proteolysis and cell size.Methods: IF and morphometric analyses were performed on heart slices from neonatal and adult normal and KO hearts. Heart denervation was induced by 6-OH-DOPA (100mg/kg). Surgical dissection of the subepi- and subendocardium was set up.Results: CM size is heterogenous throughout the mouse myocardium, with the cells in the outer layers (sEPI hereafter) being significantly larger than the similarly-oriented ones in the innermost (sENDO) layers (sEPI: 8590±2121 vs sENDO 4697±1433, in μm3; sEPI/sENDO CM size: 1.83±0.43). Such size differences, that parallel the ‘EPI-to-ENDO’; gradient in cSN density (cSNs/CM: sEPI 0.45±0.06 vs sENDO 0.15±0.02), are completely ablated upon cSN denervation (sEPI/sENDO CM size: 0.83±0.26), and are absent in both β2-AR-/- and MuRF1-/- mice. Interestingly, chronic treatment with either the β2-AR agonist clenbuterol (3mg/kg), or the β2-AR antagonist ICI118,551 (1mg/kg), which diffuse throughout the myocardium resulting in hypertrophic or atrophic remodeling, respectively, also abolish the sEPI-to-sENDO CM size difference, supporting the notion that SN control over CM morphology is operated regionally. In further support of the causal role of cSNs in controlling myocardial heterogeneity, sEPI/sENDO CMs size differences are not present immediately after birth and start to establish at P7, in parallel with the development of myocardial sympathetic innervation and, consistently, never establish in mice permanently denervated at P1. Furthermore, we demonstrated that proteolysis is differentially regulated in the sEPI and sENDO, as sympathetic denervation upregulated the muscle specific atrogenes MuRF1 and Atrogin-1 significantly more in the former than in the latter regions.Conclusions: Constitutive activity of the cardiac SNs is required for the establishment and maintenance of the correct trophic CM properties. This is the first demonstration of an otherwise homogenous tissue that is shaped by a superimposed pattern of cSNs.1. Zaglia et al. Cardiovasc Res, 2013 [ABSTRACT FROM PUBLISHER]

Published
2014
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15. 17 Inhibition of the ubiquitin ligase atrogin-1 impairs chmp2b turnover, blocks autophagy flux and causes cardiomyopathy.

Author

Zaglia, T, Milan, G, Ruhs, A, Franzoso, M, Bertaggia, E, Pianca, N, Catalucci, D, Kruger, M, Mongillo, M, and Sandri, M

Subjects
CARDIOMYOPATHIES, UBIQUITIN ligases, AUTOPHAGY, IMMUNOFLUORESCENCE, PULMONARY fibrosis, VENTRICULAR remodeling
Abstract

Purpose: Control of cardiomyocyte (CM) proteostasis operated by the ubiquitin/proteasome (UPS) and autophagy/lysosome systems is fundamental for heart adaptation to both physiologic and pathologic stresses. Reduced efficiency of either UPS or autophagy/lysosome system occurs during ageing and has been associated to cardiomyopathies. Atrogin-1 is a muscle specific ubiquitin ligase, targeting for degradation signalling proteins involved in cardiac hypertrophy. However, the role of Atrogin-1 in CM biology and its involvement in the molecular mechanism of cardiac dysfunction, are largely unexplored.Methods: We analyzed hearts from Atrogin-1 knock-out (KO) mice from 6 mo. onwards until death, and compared it to that of age- and sex-matched controls. Functional, immunofluorescence and electron microscopy analyses were performed. Markers of ER/SR stress and autophagy/lysosome systems were investigated by RTqPCR and WB. In vivo pulsed SILAC proteomics and bioinformatics, Co-IP, in vitro assays and in vivo viral silencing were performed to identify novel targets of Atrogin-1.Results: By using in vivo and in vitro assays we identified a novel target of Atrogin-1, the ESCRTIII protein CHMP2B, that plays a fundamental role in autophagy. Failure to degrade CHMP2B in Atrogin-1 KO mice caused autophagy impairment, accumulation of intracellular protein aggregates, activation of the unfolded protein response and subsequent CM apoptosis, all of which increased progressively during ageing. The alterations in cellular proteostasis resulted in cardiomyopathy with a restrictive pattern, characterized by myocardial remodelling with interstitial fibrosis, diastolic dysfunction (Edt, KO: 20.7±2.7 vs WT: 27.8±5.7, in msec), arrhythmias and secondary LA and ventricular remodelling, as well as CM hypertrophy (CM area, KO: 289.34±2.23 vs WT: 236.77±1.64, in μm2). Aged Atrogin-1 KO mice had reduced tolerance to treadmill exercise compared to controls, and shortened life span (KO: 17±1 vs WT: 24±1.2, in mo.). In vivo reduction of CHMP2B protein level in the KO mice restored normal autophagy and protected CMs from cell death resulting from CHMP2B proteotoxicity.Conclusions: Our data highlight the importance of regulated proteolysis in the heart and show that the loss of Atrogin-1 per se is sufficient to cause cardiac damage, which evolves into cardiomyopathy when protein quality control becomes less efficient, as occurring in aging. Such cardiomyopathy represents a novel model of proteotoxic myocardial remodelling and will be useful to determine the mechanism of impaired proteostasis to CM damage. [ABSTRACT FROM PUBLISHER]

Published
2014
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16. Nerve growth factor transfer from cardiomyocytes to innervating sympathetic neurons activates TrkA receptors at the neuro-cardiac junction.

Author

Dokshokova L, Franzoso M, Di Bona A, Moro N, Sanchez Alonso JL, Prando V, Sandre M, Basso C, Faggian G, Abriel H, Marin O, Gorelik J, Zaglia T, and Mongillo M

Subjects
Animals, Humans, Mice, Nerve Growth Factor metabolism, Neurons physiology, Receptor, trkA metabolism, Sympathetic Nervous System physiology, Tropomyosin metabolism, Heart Diseases metabolism, Myocytes, Cardiac physiology
Abstract

Sympathetic neurons densely innervate the myocardium with non-random topology and establish structured contacts (i.e. neuro-cardiac junctions, NCJ) with cardiomyocytes, allowing synaptic intercellular communication. Establishment of heart innervation is regulated by molecular mediators released by myocardial cells. The mechanisms underlying maintenance of cardiac innervation in the fully developed heart, are, however, less clear. Notably, several cardiac diseases, primarily affecting cardiomyocytes, are associated with sympathetic denervation, supporting the hypothesis that retrograde 'cardiomyocyte-to-sympathetic neuron' communication is essential for heart cellular homeostasis. We aimed to determine whether cardiomyocytes provide nerve growth factor (NGF) to sympathetic neurons, and the role of the NCJ in supporting such retrograde neurotrophic signalling. Immunofluorescence on murine and human heart slices shows that NGF and its receptor, tropomyosin-receptor-kinase-A, accumulate, respectively, in the pre- and post-junctional sides of the NCJ. Confocal immunofluorescence, scanning ion conductance microscopy and molecular analyses, in co-cultures, demonstrate that cardiomyocytes feed NGF to sympathetic neurons, and that this mechanism requires a stable intercellular contact at the NCJ. Consistently, cardiac fibroblasts, devoid of NCJ, are unable to sustain SN viability. ELISA assay and competition binding experiments suggest that this depends on the NCJ being an insulated microenvironment, characterized by high [NGF]. In further support, real-time imaging of tropomyosin-receptor-kinase-A vesicle movements demonstrate that efficiency of neurotrophic signalling parallels the maturation of such structured intercellular contacts. Altogether, our results demonstrate the mechanisms which link sympathetic neuron survival to neurotrophin release by directly innervated cardiomyocytes, conceptualizing sympathetic neurons as cardiomyocyte-driven heart drivers. KEY POINTS: CMs are the cell source of nerve growth factor (NGF), required to sustain innervating cardiac SNs; NCJ is the place of the intimate liaison, between SNs and CMs, allowing on the one hand neurons to peremptorily control CM activity, and on the other, CMs to adequately sustain the contacting, ever-changing, neuronal actuators; alterations in NCJ integrity may compromise the efficiency of 'CM-to-SN' signalling, thus representing a potentially novel mechanism of sympathetic denervation in cardiac diseases., (© 2022 The Authors. The Journal of Physiology published by John Wiley & Sons Ltd on behalf of The Physiological Society.)

Published
2022
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17. Tuning the Consonance of Microscopic Neuro-Cardiac Interactions Allows the Heart Beats to Play Countless Genres.

Author

Franzoso M, Dokshokova L, Vitiello L, Zaglia T, and Mongillo M

Abstract

Different from skeletal muscle, the heart autonomously generates rhythmic contraction independently from neuronal inputs. However, speed and strength of the heartbeats are continuously modulated by environmental, physical or emotional inputs, delivered by cardiac innervating sympathetic neurons, which tune cardiomyocyte (CM) function, through activation of β-adrenoceptors (β-ARs). Given the centrality of such mechanism in heart regulation, β-AR signaling has been subject of intense research, which has reconciled the molecular details of the transduction pathway and the fine architecture of cAMP signaling in subcellular nanodomains, with its final effects on CM function. The importance of mechanisms keeping the elements of β-AR/cAMP signaling in good order emerges in pathology, when the loss of proper organization of the transduction pathway leads to detuned β-AR/cAMP signaling, with detrimental consequences on CM function. Despite the compelling advancements in decoding cardiac β-AR/cAMP signaling, most discoveries on the subject were obtained in isolated cells, somehow neglecting that complexity may encompass the means in which receptors are activated in the intact heart. Here, we outline a set of data indicating that, in the context of the whole myocardium, the heart orchestra (CMs) is directed by a closely interacting and continuously attentive conductor, represented by SNs. After a roundup of literature on CM cAMP regulation, we focus on the unexpected complexity and roles of cardiac sympathetic innervation, and present the recently discovered Neuro-Cardiac Junction, as the election site of "SN-CM" interaction. We further discuss how neuro-cardiac communication is based on the combination of extra- and intra-cellular signaling micro/nano-domains, implicating neuronal neurotransmitter exocytosis, β-ARs and elements of cAMP homeostasis in CMs, and speculate on how their dysregulation may reflect on dysfunctional neurogenic control of the heart in pathology., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Franzoso, Dokshokova, Vitiello, Zaglia and Mongillo.)

Published
2022
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18. Cardiac sympathetic innervation network shapes the myocardium by locally controlling cardiomyocyte size through the cellular proteolytic machinery.

Author

Pianca N, Di Bona A, Lazzeri E, Costantini I, Franzoso M, Prando V, Armani A, Rizzo S, Fedrigo M, Angelini A, Basso C, Pavone FS, Rubart M, Sacconi L, Zaglia T, and Mongillo M

Subjects
Adult, Animals, Cells, Cultured, Coculture Techniques methods, Heart Rate physiology, Humans, Infant, Male, Mice, Mice, Inbred C57BL, Myocardium metabolism, Myocytes, Cardiac metabolism, Neurons metabolism, Neurons physiology, Signal Transduction physiology, Sympathetic Nervous System metabolism, Heart physiology, Myocytes, Cardiac physiology, Sympathetic Nervous System physiology
Abstract

Key Points: The heart is innervated by a dense sympathetic neuron network which, in the short term, controls chronotropy and inotropy and, in the long term, regulates cardiomyocyte size. Acute neurogenic control of heart rate is achieved locally through direct neuro-cardiac coupling at specific junctional sites (neuro-cardiac junctions). The ventricular sympathetic network topology is well-defined and characteristic for each mammalian species. In the present study, we used cell size regulation to determine whether long-term modulation of cardiac structure is achieved via direct sympatho-cardiac coupling. Local density of cardiac innervation correlated with cell size throughout the myocardial walls in all mammalian species analysed, including humans. The data obtained suggest that constitutive neurogenic control of cardiomyocyte trophism occurs through direct intercellular signalling at neuro-cardiac junctions., Abstract: It is widely appreciated that sympathetic stimulation of the heart involves a sharp increase in beating rate and significant enhancement of contractility. We have previously shown that, in addition to these evident functions, sympathetic neurons (SNs) also provide trophic input to cardiomyocytes (CMs), regulating cell and organ size. More recently, we have demonstrated that cardiac neurons establish direct interactions with CMs, allowing neuro-cardiac communication to occur locally, with a 'quasi-synaptic' mechanism. Based on the evidence that cardiac SNs are unevenly distributed throughout the myocardial walls, we investigated the hypothesis that CM size distribution reflects the topology of neuronal density. In vitro analyses of SN/CM co-cultures, ex vivo confocal and multiphoton imaging in clarified hearts, and biochemical and molecular approaches were employed, in both rodent and human heart biopsies. In line with the trophic effect of SNs, and with local neuro-cardiac communication, CMs, directly contacted by SNs in co-cultures, were larger than the non-targeted ones. This property reflects the distribution of CM size throughout the ventricles of intact mouse heart, in which cells in the outer myocardial layers, which were contacted by more neuronal processes, were larger than those in the less innervated subendocardial region. Such differences disappeared upon genetic or pharmacological interference with the trophic SN/CM signalling axis. Remarkably, CM size followed the SN distribution pattern in other mammals, including humans. Our data suggest that both the acute and chronic influence of SNs on cardiac function and structure is enacted as a result of the establishment of specific intercellular neuro-cardiac junctions., (© 2019 The Authors. The Journal of Physiology © 2019 The Physiological Society.)

Published
2019
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19. Dynamics of neuroeffector coupling at cardiac sympathetic synapses.

Author

Prando V, Da Broi F, Franzoso M, Plazzo AP, Pianca N, Francolini M, Basso C, Kay MW, Zaglia T, and Mongillo M

Subjects
Animals, Cell Communication, Cells, Cultured, Coculture Techniques, Heart Rate, Humans, Mice, Mice, Inbred C57BL, Mice, Transgenic, Myocytes, Cardiac cytology, Neurons cytology, Norepinephrine metabolism, Optogenetics, Rats, Rats, Sprague-Dawley, Cardiac Output, Myocytes, Cardiac physiology, Neurons physiology, Sympathetic Nervous System physiology, Synapses physiology, Synaptic Transmission
Abstract

Key Points: The present study demonstrates, by in vitro and in vivo analyses, the novel concept that signal transmission between sympathetic neurons and the heart, underlying the physiological regulation of cardiac function, operates in a quasi-synaptic fashion. This is a result of the direct coupling between neurotransmitter releasing sites and effector cardiomyocyte membranes., Abstract: Cardiac sympathetic neurons (SNs) finely tune the rate and strength of heart contractions to match blood demand, both at rest and during acute stress, through the release of noradrenaline (NE). Junctional sites at the interface between the two cell types have been observed, although whether direct neurocardiac coupling has a role in heart physiology has not been clearly demonstrated to date. We investigated the dynamics of SN/cardiomyocyte intercellular signalling, both by fluorescence resonance energy transfer-based imaging of cAMP in co-cultures, as a readout of cardiac β-adrenergic receptor activation, and in vivo, using optogenetics in transgenic mice with SN-specific expression of Channelrhodopsin-2. We demonstrate that SNs and cardiomyocytes interact at specific sites in the human and rodent heart, as well as in co-cultures. Accordingly, neuronal activation elicited intracellular cAMP increases only in directly contacted myocytes and cell-cell coupling utilized a junctional extracellular signalling domain with an elevated NE concentration. In the living mouse, optogenetic activation of cardiac SNs innervating the sino-atrial node resulted in an instantaneous chronotropic effect, which shortened the heartbeat interval with single beat precision. Remarkably, inhibition of the optogenetically elicited chronotropic responses required a high dose of propranolol (20-50 mg kg -1 ), suggesting that sympathetic neurotransmission in the heart occurs at a locally elevated NE concentration. Our in vitro and in vivo data suggest that the control of cardiac function by SNs occurs via direct intercellular coupling as a result of the establishment of a specific junctional site., (© 2018 The Authors. The Journal of Physiology © 2018 The Physiological Society.)

Published
2018
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20. Atrogin-1 deficiency promotes cardiomyopathy and premature death via impaired autophagy.

Author

Zaglia T, Milan G, Ruhs A, Franzoso M, Bertaggia E, Pianca N, Carpi A, Carullo P, Pesce P, Sacerdoti D, Sarais C, Catalucci D, Krüger M, Mongillo M, and Sandri M

Subjects
Animals, Apoptosis physiology, Cardiomyopathies pathology, Cardiomyopathies physiopathology, Disease Models, Animal, Electrocardiography, Endoplasmic Reticulum Stress, Endosomal Sorting Complexes Required for Transport antagonists & inhibitors, Endosomal Sorting Complexes Required for Transport genetics, Endosomal Sorting Complexes Required for Transport metabolism, Lysosomes metabolism, Male, Mice, Mice, Inbred C57BL, Mice, Knockout, Muscle Proteins genetics, Muscle Proteins physiology, Myocytes, Cardiac pathology, Myocytes, Cardiac physiology, Nerve Tissue Proteins antagonists & inhibitors, Nerve Tissue Proteins genetics, Nerve Tissue Proteins metabolism, Proteasome Endopeptidase Complex metabolism, SKP Cullin F-Box Protein Ligases genetics, SKP Cullin F-Box Protein Ligases physiology, Tachycardia, Ventricular etiology, Ubiquitin metabolism, Unfolded Protein Response, Autophagy physiology, Cardiomyopathies etiology, Muscle Proteins deficiency, SKP Cullin F-Box Protein Ligases deficiency
Abstract

Cardiomyocyte proteostasis is mediated by the ubiquitin/proteasome system (UPS) and autophagy/lysosome system and is fundamental for cardiac adaptation to both physiologic (e.g., exercise) and pathologic (e.g., pressure overload) stresses. Both the UPS and autophagy/lysosome system exhibit reduced efficiency as a consequence of aging, and dysfunction in these systems is associated with cardiomyopathies. The muscle-specific ubiquitin ligase atrogin-1 targets signaling proteins involved in cardiac hypertrophy for degradation. Here, using atrogin-1 KO mice in combination with in vivo pulsed stable isotope labeling of amino acids in cell culture proteomics and biochemical and cellular analyses, we identified charged multivesicular body protein 2B (CHMP2B), which is part of an endosomal sorting complex (ESCRT) required for autophagy, as a target of atrogin-1-mediated degradation. Mice lacking atrogin-1 failed to degrade CHMP2B, resulting in autophagy impairment, intracellular protein aggregate accumulation, unfolded protein response activation, and subsequent cardiomyocyte apoptosis, all of which increased progressively with age. Cellular proteostasis alterations resulted in cardiomyopathy characterized by myocardial remodeling with interstitial fibrosis, with reduced diastolic function and arrhythmias. CHMP2B downregulation in atrogin-1 KO mice restored autophagy and decreased proteotoxicity, thereby preventing cell death. These data indicate that atrogin-1 promotes cardiomyocyte health through mediating the interplay between UPS and autophagy/lysosome system and its alteration promotes development of cardiomyopathies.

Published
2014
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21. Cardiac sympathetic neurons provide trophic signal to the heart via β2-adrenoceptor-dependent regulation of proteolysis.

Author

Zaglia T, Milan G, Franzoso M, Bertaggia E, Pianca N, Piasentini E, Voltarelli VA, Chiavegato D, Brum PC, Glass DJ, Schiaffino S, Sandri M, and Mongillo M

Subjects
Animals, Atrophy, Autophagy, Cells, Cultured, Forkhead Box Protein O1, Forkhead Transcription Factors physiology, Mice, Mice, Inbred C57BL, Muscle Proteins physiology, Norepinephrine pharmacology, SKP Cullin F-Box Protein Ligases physiology, Tripartite Motif Proteins, Ubiquitin-Protein Ligases physiology, Heart innervation, Myocytes, Cardiac pathology, Proteins metabolism, Receptors, Adrenergic, beta-2 physiology, Sympathetic Nervous System physiology
Abstract

Aims: Increased cardiac sympathetic neuron (SN) activity has been associated with pathologies such as heart failure and hypertrophy, suggesting that cardiac innervation regulates cardiomyocyte trophism. Whether continuous input from the SNs is required for the maintenance of the cardiomyocyte size has not been determined thus far., Methods and Results: To address the role of cardiac innervation in cardiomyocyte size regulation, we monitored the effect of pharmacological sympathetic denervation in mice on cardiac structure, function, and signalling from 24 h to 30 days in the absence of other pathological stimuli. SN ablation caused an immediate reduction in the cardiomyocyte size with minimal consequences on the resting contractile function. Atrophic remodelling was mediated by the ubiquitin-proteasome system through FOXO-dependent early induction of the muscle-specific E3 ubiquitin ligases Atrogin-1/MAFbx and MuRF1, which was followed by activation of the autophagy-lysosome system. MuRF1 was found to be determinant in denervation atrophy as remodelling did not develop in denervated MuRF1 knock-out (KO) hearts. These effects were caused by decreased basal stimulation of cardiomyocyte β2-adrenoceptor (AR), as atrophy was prevented by treatment of denervated mice with the β2-AR agonist clenbuterol. Consistent with these data, we also observed that β2-AR KO mice showed cardiac atrophy at rest., Conclusion: Cardiac SNs are strong regulators of the cardiomyocyte size via β2-AR-dependent repression of proteolysis, demonstrating that the neuro-cardiac axis operates constitutively for the determination of the physiological cardiomyocyte size. These results are of great clinical relevance given the role of β-AR in cardiovascular diseases and their modulation in therapy.

Published
2013
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22. Microfluidic-driven viral infection on cell cultures: Theoretical and experimental study.

Author

Cimetta E, Franzoso M, Trevisan M, Serena E, Zambon A, Giulitti S, Barzon L, and Elvassore N

Abstract

Advanced cell culture systems creating a controlled and predictable microenvironment together with computational modeling may be useful tools to optimize the efficiency of cell infections. In this paper, we will present a phenomenological study of a virus-host infection system, and the development of a multilayered microfluidic platform used to accurately tune the virus delivery from a diffusive-limited regime to a convective-dominated regime. Mathematical models predicted the convective-diffusive regimes developed within the system itself and determined the dominating mass transport phenomena. Adenoviral vectors carrying the enhanced green fluorescent protein (EGFP) transgene were used at different multiplicities of infection (MOI) to infect multiple cell types, both in standard static and in perfused conditions. Our results validate the mathematical models and demonstrate how the infection processes through perfusion via microfluidic platform led to an enhancement of adenoviral infection efficiency even at low MOIs. This was particularly evident at the longer time points, since the establishment of steady-state condition guaranteed a constant viral concentration close to cells, thus strengthening the efficiency of infection. Finally, we introduced the concept of effective MOI, a more appropriate variable for microfluidic infections that considers the number of adenoviruses in solution per cell at a certain time.

Published
2012
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