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5. Cardiac metabolism as a driver and therapeutic target of myocardial infarction

Author

Zuurbier, C.J. Bertrand, L. Beauloye, C.R. Andreadou, I. Ruiz-Meana, M. Jespersen, N.R. Kula-Alwar, D. Prag, H.A. Eric Botker, H. Dambrova, M. Montessuit, C. Kaambre, T. Liepinsh, E. Brookes, P.S. Krieg, T.

Abstract

Reducing infarct size during a cardiac ischaemic-reperfusion episode is still of paramount importance, because the extension of myocardial necrosis is an important risk factor for developing heart failure. Cardiac ischaemia-reperfusion injury (IRI) is in principle a metabolic pathology as it is caused by abruptly halted metabolism during the ischaemic episode and exacerbated by sudden restart of specific metabolic pathways at reperfusion. It should therefore not come as a surprise that therapy directed at metabolic pathways can modulate IRI. Here, we summarize the current knowledge of important metabolic pathways as therapeutic targets to combat cardiac IRI. Activating metabolic pathways such as glycolysis (eg AMPK activators), glucose oxidation (activating pyruvate dehydrogenase complex), ketone oxidation (increasing ketone plasma levels), hexosamine biosynthesis pathway (O-GlcNAcylation; administration of glucosamine/glutamine) and deacetylation (activating sirtuins 1 or 3; administration of NAD+-boosting compounds) all seem to hold promise to reduce acute IRI. In contrast, some metabolic pathways may offer protection through diminished activity. These pathways comprise the malate-aspartate shuttle (in need of novel specific reversible inhibitors), mitochondrial oxygen consumption, fatty acid oxidation (CD36 inhibitors, malonyl-CoA decarboxylase inhibitors) and mitochondrial succinate metabolism (malonate). Additionally, protecting the cristae structure of the mitochondria during IR, by maintaining the association of hexokinase II or creatine kinase with mitochondria, or inhibiting destabilization of FOF1-ATPase dimers, prevents mitochondrial damage and thereby reduces cardiac IRI. Currently, the most promising and druggable metabolic therapy against cardiac IRI seems to be the singular or combined targeting of glycolysis, O-GlcNAcylation and metabolism of ketones, fatty acids and succinate. © 2020 The Authors. Journal of Cellular and Molecular Medicine published by Foundation for Cellular and Molecular Medicine and John Wiley & Sons Ltd

Published
2020

6. Practical guidelines for rigor and reproducibility in preclinical and clinical studies on cardioprotection

Author

Bøtker, H.E. Hausenloy, D. Andreadou, I. Antonucci, S. Boengler, K. Davidson, S.M. Deshwal, S. Devaux, Y. Di Lisa, F. Di Sante, M. Efentakis, P. Femminò, S. García-Dorado, D. Giricz, Z. Ibanez, B. Iliodromitis, E. Kaludercic, N. Kleinbongard, P. Neuhäuser, M. Ovize, M. Pagliaro, P. Rahbek-Schmidt, M. Ruiz-Meana, M. Schlüter, K.-D. Schulz, R. Skyschally, A. Wilder, C. Yellon, D.M. Ferdinandy, P. Heusch, G.

Published
2018

7. Ischaemic conditioning and targeting reperfusion injury: a 30 year voyage of discovery

Author

Hausenloy D., Barrabes J., Bøtker H., Davidson S., Di Lisa F., Downey J., Engstrom T., Ferdinandy P., Carbrera-Fuentes H., Heusch G., Ibanez B., Iliodromitis E., Inserte J., Jennings R., Kalia N., Kharbanda R., Lecour S., Marber M., Miura T., Ovize M., Perez-Pinzon M., Piper H., Przyklenk K., Schmidt M., Redington A., Ruiz-Meana M., Vilahur G., Vinten-Johansen J., Yellon D., and Garcia-Dorado D.

Subjects
Myocardial reperfusion injury, RISK and SAFE pathway, Ischaemic conditioning, Cardioprotection, Mitochondria
Abstract

© 2016, The Author(s).To commemorate the auspicious occasion of the 30th anniversary of IPC, leading pioneers in the field of cardioprotection gathered in Barcelona in May 2016 to review and discuss the history of IPC, its evolution to IPost and RIC, myocardial reperfusion injury as a therapeutic target, and future targets and strategies for cardioprotection. This article provides an overview of the major topics discussed at this special meeting and underscores the huge importance and impact, the discovery of IPC has made in the field of cardiovascular research.

Published
2016

8. Ischaemic conditioning and targeting reperfusion injury: a 30 year voyage of discovery

Author

Hausenloy, D.J. Barrabes, J.A. Bøtker, H.E. Davidson, S.M. Di Lisa, F. Downey, J. Engstrom, T. Ferdinandy, P. Carbrera-Fuentes, H.A. Heusch, G. Ibanez, B. Iliodromitis, E.K. Inserte, J. Jennings, R. Kalia, N. Kharbanda, R. Lecour, S. Marber, M. Miura, T. Ovize, M. Perez-Pinzon, M.A. Piper, H.M. Przyklenk, K. Schmidt, M.R. Redington, A. Ruiz-Meana, M. Vilahur, G. Vinten-Johansen, J. Yellon, D.M. Garcia-Dorado, D.

Abstract

To commemorate the auspicious occasion of the 30th anniversary of IPC, leading pioneers in the field of cardioprotection gathered in Barcelona in May 2016 to review and discuss the history of IPC, its evolution to IPost and RIC, myocardial reperfusion injury as a therapeutic target, and future targets and strategies for cardioprotection. This article provides an overview of the major topics discussed at this special meeting and underscores the huge importance and impact, the discovery of IPC has made in the field of cardiovascular research. © 2016, The Author(s).

Published
2016

14. ESC Working Group Cellular Biology of the Heart: Position Paper: improving the preclinical assessment of novel cardioprotective therapies

Author

Lecour, S., primary, Botker, H. E., additional, Condorelli, G., additional, Davidson, S. M., additional, Garcia-Dorado, D., additional, Engel, F. B., additional, Ferdinandy, P., additional, Heusch, G., additional, Madonna, R., additional, Ovize, M., additional, Ruiz-Meana, M., additional, Schulz, R., additional, Sluijter, J. P. G., additional, Van Laake, L. W., additional, Yellon, D. M., additional, and Hausenloy, D. J., additional

Published
2014
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22. Sunday, 18 July 2010

Author

Schuchardt, M., primary, Toelle, M., additional, Huang, T., additional, Wiedon, A., additional, Van Der Giet, M., additional, Mill, C., additional, George, S., additional, Jeremy, J., additional, Santulli, G., additional, Illario, M., additional, Cipolletta, E., additional, Sorriento, D., additional, Del Giudice, C., additional, Anastasio, A., additional, Trimarco, B., additional, Iaccarino, G., additional, Jobs, A., additional, Wagner, C., additional, Kurtz, A., additional, De Wit, C., additional, Koller, A., additional, Suvorava, T., additional, Weber, M., additional, Dao, V., additional, Kojda, G., additional, Tsaousi, A., additional, Lyon, C., additional, Williams, H., additional, Barth, N., additional, Loot, A., additional, Fleming, I., additional, Keul, P., additional, Lucke, S., additional, Graeler, M., additional, Heusch, G., additional, Levkau, B., additional, Biessen, E., additional, De Jager, S., additional, Bermudez-Pulgarin, B., additional, Bot, I., additional, Abia, R., additional, Van Berkel, T., additional, Renger, A., additional, Noack, C., additional, Zafiriou, M., additional, Dietz, R., additional, Bergmann, M., additional, Zelarayan, L., additional, Hammond, J., additional, Hamelet, J., additional, Van Assche, T., additional, Belge, C., additional, Vanderper, A., additional, Langin, D., additional, Herijgers, P., additional, Balligand, J., additional, Perrot, A., additional, Neubert, M., additional, Posch, M., additional, Oezcelik, C., additional, Waldmuller, S., additional, Berger, F., additional, Scheffold, T., additional, Bouvagnet, P., additional, Ozcelik, C., additional, Lebreiro, A., additional, Martins, E., additional, Lourenco, P., additional, Cruz, C., additional, Martins, M., additional, Bettencourt, P., additional, Maciel, M., additional, Abreu-Lima, C., additional, Pilichou, K., additional, Bauce, B., additional, Rampazzo, A., additional, Carturan, E., additional, Corrado, D., additional, Thiene, G., additional, Basso, C., additional, Piccini, I., additional, Fortmueller, L., additional, Kuhlmann, M., additional, Schaefers, M., additional, Carmeliet, P., additional, Kirchhof, P., additional, Fabritz, L., additional, Sanchez, J., additional, Rodriguez-Sinovas, A., additional, Agullo, E., additional, Garcia-Dorado, D., additional, Lymperopoulos, A., additional, Rengo, G., additional, Gao, E., additional, Zincarelli, C., additional, Koch, W., additional, Morgan, P., additional, Diez, A., additional, Perez, N., additional, Cingolani, H., additional, Zahradnikova, A., additional, Polakova, E., additional, Zahradnik, I., additional, Fluschnik, N., additional, Sossalla, S., additional, Ort, K., additional, Neef, S., additional, Hasenfuss, G., additional, Maier, L., additional, Weinert, S., additional, Poitz, D., additional, Herold, J., additional, Schmeisser, A., additional, Strasser, J., additional, Braun-Dullaeus, R., additional, Nazari-Jahantigh, M., additional, Weber, C., additional, Schober, A., additional, Leuner, A., additional, Eichhorn, B., additional, Ravens, U., additional, Morawietz, H., additional, Babes, E., additional, Babes, V., additional, Popescu, M., additional, Ardelean, A., additional, Rus, M., additional, Bustea, C., additional, Gwozdz, P., additional, Csanyi, G., additional, Luzak, B., additional, Gajda, M., additional, Mateuszuk, L., additional, Chmura-Skirlinska, A., additional, Watala, C., additional, Chlopicki, S., additional, Kierzkowska, I., additional, Sulicka, J., additional, Kwater, A., additional, Strach, M., additional, Surdacki, A., additional, Siedlar, M., additional, Grodzicki, T., additional, Olieslagers, S., additional, Pardali, L., additional, Tchaikovski, V., additional, Ten Dijke, P., additional, Waltenberger, J., additional, Renner, M., additional, Redwan, B., additional, Winter, M., additional, Panzenboeck, A., additional, Jakowitsch, J., additional, Sadushi-Kolici, R., additional, Bonderman, D., additional, Lang, I., additional, Toso, A., additional, Tanini, L., additional, Pizzetti, T., additional, Leoncini, M., additional, Maioli, M., additional, Tedeschi, D., additional, Oliviero, C., additional, Bellandi, F., additional, Casprini, P., additional, Amato, M., additional, Molins, B., additional, Pena, E., additional, Badimon, L., additional, Ferreiro Gutierrez, J., additional, Ueno, M., additional, Alissa, R., additional, Dharmashankar, K., additional, Capodanno, D., additional, Desai, B., additional, Bass, T., additional, Angiolillo, D., additional, Chabielska, E., additional, Gromotowicz, A., additional, Szemraj, J., additional, Stankiewicz, A., additional, Zakrzeska, A., additional, Mohammed, S., additional, Molla, F., additional, Soldo, A., additional, Russo, I., additional, Germano, G., additional, Balconi, G., additional, Staszewsky, L., additional, Latini, R., additional, Lynch, F., additional, Austin, C., additional, Prendergast, B., additional, Keenan, D., additional, Malik, R., additional, Izzard, A., additional, Heagerty, A., additional, Czikora, A., additional, Lizanecz, E., additional, Rutkai, I., additional, Boczan, J., additional, Porszasz, R., additional, Papp, Z., additional, Edes, I., additional, Toth, A., additional, Colantuoni, A., additional, Vagnani, S., additional, Lapi, D., additional, Maroz-Vadalazhskaya, N., additional, Koslov, I., additional, Shumavetz, V., additional, Glibovskaya, T., additional, Ostrovskiy, Y., additional, Koutsiaris, A., additional, Tachmitzi, S., additional, Kotoula, M., additional, Giannoukas, A., additional, Tsironi, E., additional, Darago, A., additional, Orosz, P., additional, Megyesi, Z., additional, Schudeja, S., additional, Matschke, K., additional, Deussen, A., additional, Castro, M., additional, Cena, J., additional, Walsh, M., additional, Schulz, R., additional, Poddar, K., additional, Rha, S., additional, Ramasamy, S., additional, Park, J., additional, Choi, C., additional, Seo, H., additional, Park, C., additional, Oh, D., additional, Almeida, J., additional, Pimenta, S., additional, Bernardes, J., additional, Machado, J., additional, Sabatasso, S., additional, Laissue, J., additional, Hlushchuk, R., additional, Brauer-Krisch, E., additional, Bravin, A., additional, Blattmann, H., additional, Michaud, K., additional, Djonov, V., additional, Hirschberg, K., additional, Tarcea, V., additional, Pali, S., additional, Korkmaz, S., additional, Loganathan, S., additional, Merkely, B., additional, Karck, M., additional, Szabo, G., additional, Pagliani, L., additional, Faggin, E., additional, Rattazzi, M., additional, Puato, M., additional, Presta, M., additional, Grego, F., additional, Deriu, G., additional, Pauletto, P., additional, Kaiser, R., additional, Albrecht, K., additional, Schgoer, W., additional, Theurl, M., additional, Beer, A., additional, Wiedemann, D., additional, Steger, C., additional, Bonaros, N., additional, Kirchmair, R., additional, Kharlamov, A., additional, Cabaravdic, M., additional, Breuss, J., additional, Uhrin, P., additional, Binder, B., additional, Fiordaliso, F., additional, Maggioni, M., additional, Biondi, A., additional, Masson, S., additional, Cervo, L., additional, Francke, A., additional, Soenke, W., additional, Strasser, R., additional, Hecht, N., additional, Vajkoczy, P., additional, Woitzik, J., additional, Hackbusch, D., additional, Gatzke, N., additional, Duelsner, A., additional, Tsuprykov, O., additional, Slavic, S., additional, Buschmann, I., additional, Kappert, K., additional, Massaro, M., additional, Scoditti, E., additional, Carluccio, M., additional, Storelli, C., additional, Distante, A., additional, De Caterina, R., additional, Barandi, L., additional, Harmati, G., additional, Simko, J., additional, Horvath, B., additional, Szentandrassy, N., additional, Banyasz, T., additional, Magyar, J., additional, Nanasi, P., additional, Kaya, A., additional, Uzunhasan, I., additional, Yildiz, A., additional, Yigit, Z., additional, Turkoglu, C., additional, Doisne, N., additional, Zannad, N., additional, Hivert, B., additional, Cosnay, P., additional, Maupoil, V., additional, Findlay, I., additional, Virag, L., additional, Kristof, A., additional, Koncz, I., additional, Szel, T., additional, Jost, N., additional, Biliczki, P., additional, Papp, J., additional, Varro, A., additional, Bukowska, A., additional, Skopp, K., additional, Hammwoehner, M., additional, Huth, C., additional, Bode-Boeger, S., additional, Goette, A., additional, Workman, A., additional, Dempster, J., additional, Marshall, G., additional, Rankin, A., additional, Revnic, C., additional, Ginghina, C., additional, Revnic, F., additional, Yakushev, S., additional, Petrushanko, I., additional, Makhro, A., additional, Segato Komniski, M., additional, Mitkevich, V., additional, Makarov, A., additional, Gassmann, M., additional, Bogdanova, A., additional, Rutkovskiy, A., additional, Mariero, L., additional, Stenslokken, K., additional, Valen, G., additional, Vaage, J., additional, Dizayee, S., additional, Kaestner, S., additional, Kuck, F., additional, Piekorz, R., additional, Hein, P., additional, Matthes, J., additional, Nurnberg, B., additional, Herzig, S., additional, Hertel, F., additional, Switalski, A., additional, Bender, K., additional, Kienitz, M.-C., additional, Pott, L., additional, Fornai, L., additional, Angelini, A., additional, Erika Amstalden Van Hove, E., additional, Fedrigo, M., additional, Heeren, R., additional, Kruse, M., additional, Pongs, O., additional, Lehmann, H., additional, Martens-Lobenhoffer, J., additional, Roehl, F., additional, Radicke, S., additional, Cotella, C., additional, Sblattero, D., additional, Schaefer, M., additional, Wettwer, E., additional, Santoro, C., additional, Seyler, C., additional, Kulzer, M., additional, Zitron, E., additional, Scholz, E., additional, Welke, F., additional, Thomas, D., additional, Karle, C., additional, Schmidt, K., additional, Dobrev, D., additional, Houshmand, N., additional, Menesi, D., additional, Cotella, D., additional, Szuts, V., additional, Puskas, L., additional, Kiss, I., additional, Deak, F., additional, Tereshchenko, S., additional, Gladyshev, M., additional, Kalachova, G., additional, Syshchik, N., additional, Gogolashvili, N., additional, Dedok, E., additional, Evert, L., additional, Wenzel, J., additional, Brandenburger, M., additional, Bogdan, R., additional, Richardt, D., additional, Reppel, M., additional, Hescheler, J., additional, Dendorfer, A., additional, Terlau, H., additional, Wiegerinck, R., additional, Galvez-Monton, C., additional, Jorge, E., additional, Martinez, R., additional, Ricart, E., additional, Cinca, J., additional, Bagavananthem Andavan, G., additional, Lemmens Gruber, R., additional, Brack, K., additional, Coote, J., additional, Ng, G., additional, Daimi, H., additional, Haj Khelil, A., additional, Neji, A., additional, Ben Hamda, K., additional, Maaoui, S., additional, Aranega, A., additional, Chibani, J., additional, Franco Jaime, D., additional, Tanko, A.-S., additional, Daniel, J.-M., additional, Bielenberg, W., additional, Stieger, P., additional, Tillmanns, H., additional, Sedding, D., additional, Fortini, C., additional, Toffoletto, B., additional, Fucili, A., additional, Beltrami, A., additional, Fiorelli, V., additional, Francolini, G., additional, Ferrari, R., additional, Beltrami, C., additional, Castellani, C., additional, Ravara, B., additional, Tavano, R., additional, Vettor, R., additional, De Coppi, P., additional, Papini, E., additional, Gunetti, M., additional, Fagioli, F., additional, Suffredini, S., additional, Sartiani, L., additional, Stillitano, F., additional, Mugelli, A., additional, Cerbai, E., additional, Krausgrill, B., additional, Halbach, M., additional, Soemantri, S., additional, Schenk, K., additional, Lange, N., additional, Saric, T., additional, Muller-Ehmsen, J., additional, Kavanagh, D., additional, Zhao, Y., additional, Yemm, A., additional, Kalia, N., additional, Wright, E., additional, Farrell, K., additional, Wallrapp, C., additional, Geigle, P., additional, Lewis, A., additional, Stratford, P., additional, Malik, N., additional, Holt, C., additional, Raths, M., additional, Zagallo, M., additional, Luni, C., additional, Serena, E., additional, Cimetta, E., additional, Zatti, S., additional, Giobbe, G., additional, Elvassore, N., additional, Zaglia, T., additional, Zambon, A., additional, Gordon, K., additional, Mioulane, M., additional, Foldes, G., additional, Ali, N., additional, Harding, S., additional, Gorbe, A., additional, Szunyog, A., additional, Varga, Z., additional, Pirity, M., additional, Rungaruniert, S., additional, Dinnyes, A., additional, Csont, T., additional, Ferdinandy, P., additional, Iqbal, A., additional, Schneider, M. D., additional, Khodjaeva, E., additional, Ibadov, R., additional, Khalikulov, K., additional, Mansurov, A., additional, Astvatsatryan, A., additional, Senan, M., additional, Nemeth, A., additional, Lenkey, Z., additional, Ajtay, Z., additional, Cziraki, A., additional, Sulyok, E., additional, Horvath, I., additional, Lobenhoffer, J., additional, Bode-Boger, S., additional, Li, J., additional, He, Y., additional, Yang, X., additional, Wang, F., additional, Xu, H., additional, Li, X., additional, Zhao, X., additional, Lin, Y., additional, Juszynski, M., additional, Ciszek, B., additional, Jablonska, A., additional, Stachurska, E., additional, Ratajska, A., additional, Atkinson, A., additional, Inada, S., additional, Sleiman, R., additional, Zhang, H., additional, Boyett, M., additional, Dobrzynski, H., additional, Fedorenko, O., additional, Hao, G., additional, Yanni, J., additional, Buckley, D., additional, Anderson, R., additional, Ma, Y., additional, Ma, X., additional, Hu, Y., additional, Yang, Y., additional, Huang, D., additional, Liu, F., additional, Huang, Y., additional, Liu, C., additional, Jedrzejczyk, T., additional, Balwicki, L., additional, Wierucki, L., additional, Zdrojewski, T., additional, Agarkova, I., additional, Vogel, J., additional, Korybalska, K., additional, Pyda, M., additional, Witowski, J., additional, Ibatov, A., additional, Sozmen, N., additional, Seymen, A., additional, Tuncay, E., additional, Turan, B., additional, Chen, B., additional, Houston-Feenstra, L., additional, Chiong, J. R., additional, Jutzy, K., additional, Furundzija, V., additional, Kaufmann, J., additional, Meyborg, H., additional, Fleck, E., additional, Stawowy, P., additional, Ksiezycka-Majczynska, E., additional, Lubiszewska, B., additional, Kruk, M., additional, Kurjata, P., additional, Ruzyllo, W., additional, Driesen, R., additional, Coenen, T., additional, Fagard, R., additional, Sipido, K., additional, Petrov, V., additional, Aksentijevic, D., additional, Lygate, C., additional, Makinen, K., additional, Sebag-Montefiore, L., additional, Medway, D., additional, Schneider, J., additional, Neubauer, S., additional, Gasser, R., additional, Holzwart, E., additional, Rainer, P., additional, Von Lewinski, D., additional, Maechler, H., additional, Gasser, S., additional, Roessl, U., additional, Pieske, B., additional, Krueger, J., additional, Kintscher, U., additional, Podramagi, T., additional, Paju, K., additional, Piirsoo, A., additional, Roosimaa, M., additional, Kadaja, L., additional, Orlova, E., additional, Ruusalepp, A., additional, Seppet, E., additional, Auquier, J., additional, Ginion, A., additional, Hue, L., additional, Horman, S., additional, Beauloye, C., additional, Vanoverschelde, J., additional, Bertrand, L., additional, Fekete, V., additional, Zvara, A., additional, Pipis, J., additional, Konya, C., additional, Csonka, C., additional, Kraigher-Krainer, E., additional, Von Lewinksi, D., additional, Gonzalez-Loyola, A., additional, Barba, I., additional, Fernandez-Sanz, C., additional, Ruiz-Meana, M., additional, Forteza, M., additional, Bodi Peris, V., additional, Monleon, D., additional, Mainar, L., additional, Morales, J., additional, Moratal, D., additional, Trapero, I., additional, Chorro, F., additional, Leszek, P., additional, Sochanowicz, B., additional, Szperl, M., additional, Kolsut, P., additional, Piotrowski, W., additional, Rywik, T., additional, Danko, B., additional, Kruszewski, M., additional, Stanley, W., additional, Khairallah, R., additional, Khanna, N., additional, O'shea, K., additional, Kristian, T., additional, Hecker, P., additional, Des Rosiers, R., additional, Fiskum, G., additional, Fernandez-Alfonso, M., additional, Guzman-Ruiz, R., additional, Somoza, B., additional, Gil-Ortega, M., additional, Attane, C., additional, Castan-Laurell, I., additional, Valet, P., additional, Ruiz-Gayo, M., additional, Denissevich, T., additional, Schrepper, A., additional, Schwarzer, M., additional, Amorim, P., additional, Schoepe, M., additional, Mohr, F., additional, Doenst, T., additional, Chiellini, G., additional, Ghelardoni, S., additional, Saba, A., additional, Marchini, M., additional, Frascarelli, S., additional, Raffaelli, A., additional, Scanlan, T., additional, Zucchi, R., additional, Van Den Akker, N., additional, Molin, D., additional, Kolk, F., additional, Jeukens, F., additional, Olde Engberink, R., additional, Post, M., additional, Verbruggen, S., additional, Schulten, H., additional, Rochais, F., additional, Kelly, R., additional, Aberg, M., additional, Johnell, M., additional, Wickstrom, M., additional, Siegbahn, A., additional, Dimitrakis, P., additional, Groppalli, V., additional, Ott, D., additional, Seifriz, F., additional, Suter, T., additional, Zuppinger, C., additional, Kashcheyeu, Y., additional, Mueller, R., additional, Wiesen, M., additional, Gruendemann, D., additional, Falcao-Pires, I., additional, Fontes-Sousa, A., additional, Lopes-Conceicao, L., additional, Bras-Silva, C., additional, Leite-Moreira, A., additional, Bukauskas, F., additional, Palacios-Prado, N., additional, Norheim, F., additional, Raastad, T., additional, Thiede, B., additional, Drevon, C., additional, Haugen, F., additional, Lindner, D., additional, Westermann, D., additional, Zietsch, C., additional, Schultheiss, H.-P., additional, Tschoepe, C., additional, Horn, M., additional, Graham, H., additional, Hall, M., additional, Richards, M., additional, Clarke, J., additional, Dibb, K., additional, Trafford, A., additional, Cheng, C.-F., additional, Lin, H., additional, Eigeldiger-Berthou, S., additional, Buntschu, P., additional, Frobert, A., additional, Flueck, M., additional, Tevaearai, H., additional, Kadner, A., additional, Mikhailov, A., additional, Torrado, M., additional, Centeno, A., additional, Lopez, E., additional, Lourido, L., additional, Castro Beiras, A., additional, Popov, T., additional, Srdanovic, I., additional, Petrovic, M., additional, Canji, T., additional, Kovacevic, M., additional, Jovelic, A., additional, Sladojevic, M., additional, Panic, G., additional, Kararigas, G., additional, Fliegner, D., additional, Regitz-Zagrosek, V., additional, De La Rosa Sanchez, A., additional, Dominguez, J., additional, Sedmera, D., additional, Franco, D., additional, Medunjanin, S., additional, Burgbacher, F., additional, Han, W., additional, Zhang, J., additional, Gao, X., additional, Bayliss, C., additional, Song, W., additional, Stuckey, D., additional, Dyer, E., additional, Leung, M.-C., additional, Monserrat, L., additional, Marston, S., additional, Fusco, A., additional, Paillard, M., additional, Liang, J., additional, Strub, G., additional, Gomez, L., additional, Hait, N., additional, Allegood, J., additional, Lesnefsky, E., additional, Spiegel, S., additional, Zuchi, C., additional, Coiro, S., additional, Bettini, M., additional, Ciliberti, G., additional, Mancini, I., additional, Tritto, I., additional, Becker, L., additional, Ambrosio, G., additional, Adam, T., additional, Sharp, S., additional, Opie, L., additional, Lecour, S., additional, Khaliulin, I., additional, Parker, J., additional, Halestrap, A., additional, Kandasamy, A., additional, Osterholt, M., additional, Miro-Casas, E., additional, Boengler, K., additional, Menazza, S., additional, Canton, M., additional, Sheeran, F., additional, Di Lisa, F., additional, Pepe, S., additional, Borchi, E., additional, Manni, M., additional, Bargelli, V., additional, Giordano, C., additional, D'amati, G., additional, Nediani, C., additional, Raimondi, L., additional, Micova, P., additional, Balkova, P., additional, Kolar, F., additional, Neckar, J., additional, Novak, F., additional, Novakova, O., additional, Schuchardt, M., additional, Pruefer, N., additional, Pruefer, J., additional, Jankowski, V., additional, Jankowski, J., additional, Su, Y., additional, Zervou, S., additional, Seidel, B., additional, Radovits, T., additional, Barnucz, E., additional, Aggeli, I., additional, Kefaloyianni, E., additional, Beis, I., additional, Gaitanaki, C., additional, Lacerda, L., additional, Somers, S., additional, Paur, H., additional, Nikolaev, V., additional, Lyon, A., additional, Silva, S., additional, Gomes, M., additional, Ferreira, P., additional, Capuano, V., additional, Ferron, L., additional, Ruchon, Y., additional, Ben Mohamed, F., additional, Renaud, J.-F., additional, Goncalves, N., additional, Gavina, C., additional, Pinho, S., additional, Moura, C., additional, Amorim, M., additional, Pinho, P., additional, Christ, T., additional, Molenaar, P., additional, Kaumann, A., additional, Kletsiou, E., additional, Giannakopoulou, M., additional, Bozas, E., additional, Iliodromitis, E., additional, Anastasiou-Nana, M., additional, Papathanassoglou, E., additional, Chottova Dvorakova, M., additional, Mistrova, E., additional, Slavikova, J., additional, Hynie, S., additional, Sida, P., additional, Klenerova, V., additional, Zakrzewicz, A., additional, Hoffmann, C., additional, Hohberg, M., additional, Chlench, S., additional, Maroski, J., additional, Drab, M., additional, Siegel, G., additional, Pries, A., additional, Schrot, G., additional, Wilck, N., additional, Fechner, M., additional, Arias, A., additional, Meiners, S., additional, Baumann, G., additional, Stangl, V., additional, Stangl, K., additional, Ludwig, A., additional, Christ, A., additional, Eijgelaar, W., additional, Daemen, M., additional, Penfold, M., additional, Schall, T., additional, Hintenberger, R., additional, Kaun, C., additional, Pfaffenberger, S., additional, Maurer, G., additional, Huber, K., additional, Wojta, J., additional, Demyanets, S., additional, Titov, V., additional, Chin-Dusting, J., additional, Vaisman, B., additional, Khong, S., additional, Remaley, A., additional, Andrews, K., additional, Hoeper, A., additional, Khalid, A., additional, Fuglested, B., additional, Aasum, E., additional, Larsen, T., additional, Diebold, I., additional, Petry, A., additional, Djordjevic, T., additional, Belaiba, R., additional, Fratz, S., additional, Hess, J., additional, Kietzmann, T., additional, Goerlach, A., additional, Chess, D., additional, Walsh, K., additional, Van Der Velden, J., additional, Moreira-Goncalves, D., additional, Paulus, W., additional, Niessen, H., additional, Perlini, S., additional, Azibani, F., additional, Tournoux, F., additional, Fazal, L., additional, Polidano, E., additional, Merval, R., additional, Chatziantoniou, C., additional, Samuel, J., additional, Delcayre, C., additional, Mgandela, P., additional, Brooksbank, R., additional, Maswanganyi, T., additional, Woodiwiss, A., additional, Norton, G., additional, Makaula, S., additional, Bucciantini, M., additional, Spinelli, V., additional, Coppini, R., additional, Russo, E., additional, Stefani, M., additional, Sukumaran, V., additional, Watanabe, K., additional, Ma, M., additional, Thandavarayan, R., additional, Azrozal, W., additional, Sari, F., additional, Shimazaki, H., additional, Kobayashi, Y., additional, Roleder, T., additional, Golba, K., additional, Deja, M., additional, Malinowski, M., additional, Wos, S., additional, Grebe, M., additional, Preissner, K., additional, Ercan, E., additional, Guven, A., additional, Asgun, F., additional, Ickin, M., additional, Ercan, F., additional, Kaplan, A., additional, Yavuz, O., additional, Bagla, S., additional, Kuka, J., additional, Vilskersts, R., additional, Vavers, E., additional, Liepins, E., additional, Dambrova, M., additional, Duerr, G., additional, Suchan, G., additional, Heuft, T., additional, Klaas, T., additional, Zimmer, A., additional, Welz, A., additional, Fleischmann, B., additional, Dewald, O., additional, Voelkl, J., additional, Haubner, B., additional, Kremser, C., additional, Mayr, A., additional, Klug, G., additional, Reiner, M., additional, Pachinger, O., additional, Metzler, B., additional, Pisarenko, O., additional, Shulzhenko, V., additional, Pelogeykina, Y., additional, Khatri, D., additional, Studneva, I., additional, Bencsik, P., additional, Kocsis, G., additional, Shamloo, M., additional, Woodburn, K., additional, Szucs, G., additional, Kupai, K., additional, Csont, C., additional, Kocsisne Fodor, G., additional, Monostori, P., additional, and Turi, S., additional

Published
2010
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27. Sodium/Hydrogen Exchanger Inhibition Reduces Myocardial Reperfusion Edema After Normothermic Cardioplegia

Author

Tritto, F.P., Inserte, J., Garcia-Dorado, D., Ruiz-Meana, M., and Soler-Soler, J.

Abstract

Objective: The hypothesis was that Na^+/H^+ exchange occurring during normothermic cardioplegia contributes to the development of myocardial edema during subsequent reperfusion and impairs functional recovery. Methods: Rat hearts were perfused in a Langendorff apparatus and submitted to 60 minutes of normothermic cardioplegia and 90 minutes of reperfusion. Hearts were allocated to one of four groups (n = 8): inhibition of Na^+/H^+ exchanger with HOE642 throughout the whole experiment (HOE group), only during cardioplegia (HOE-C) or during reperfusion (HOE-R), and a control group. Results: In HOE and HOE-C groups, myocardial water content at the end of reperfusion was lower than in the HOE-R and control groups (526 +/- 19 and 533 +/- 18 ml/100 gm dry tissue vs 632 +/- 25 and 634 +/- 17 ml/100 gm dry tissue, respectively, p = 0.001), left ventricular end-diastolic pressure increased less after reperfusion (46.6 +/- 9.7 and 63.2 +/- 10.0 mm Hg vs 75.1 +/- 4.3 mm Hg and 85.7 +/- 8.9 mm Hg, respectively, p = 0.006), and recovery of left ventricular developed pressure was better (46.7% and 45.8% vs 4.5% and 9.8%, p = 0.048). Relative to the control group, total lactate dehydrogenase release during reperfusion was reduced by 80.2%, 69.3% and 36% in HOE, HOE-C, and HOE-R groups, respectively. Conclusion: Inhibition of the Na^+/H^+ exchange during normothermic cardioplegia reduces myocardial edema and necrosis during subsequent reperfusion, improving functional recovery. Inhibition of Na^+/H^+ exchange during reperfusion only has a much smaller effect. (J Thorac Cardiovasc Surg 1998;115:709-15)

Published
1998
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28. P441 Defective SR-mitochondria interaction and Ca2+ transfer in aged mouse cardiomyocytes.

Author

Fernandez-Sanz, C, Ruiz-Meana, M, Miro-Casas, E, Castellano, J, Barba, I, Nunez, E, Vazquez, J, and Garcia-Dorado, D

Subjects
*SARCOPLASMIC reticulum, *MITOCHONDRIA, *HEART cells, *DISEASE susceptibility, *ARTIFICIAL respiration, *LABORATORY mice
Abstract

Mitochondrial alterations are critically involved in the increased susceptibility to disease of the aging heart. We investigated the role of sarcoplasmic reticulum (SR)-mitochondria communication in myocardial calcium handling during aging.Methods and results: In subsarcolemmal and interfibrillar mitochondria isolated from old (>20 months) and young (<6 months) mouse hearts no differences in resting respiration through the different complexes were detected, but maximal ADP-stimulated O2 consumption was reduced in aged interfibrillar mitochondria. Accordingly, resting mitochondrial membrane potential in cardiomyocytes and ATP/phosphocreatine in intact myocardium (NMR spectroscopy) were preserved in old mice. Second generation proteomics disclosed an increase in mitochondrial protein oxidation during aging. Since mitochondrial Ca2+ regulates both energy production and oxidative status, we investigated whether aging affects mitochondrial Ca2+ uptake. No age-dependent differences were found in Ca2+ uptake kinetics in isolated mitochondria. By contrast, mitochondrial Ca2+ uptake resulting from SR transfer was significantly reduced in old cardiomyocytes, despite no changes in SR Ca2+ content. Immunocolocalization and proximity ligation assay identified defective communication between mitochondrial VDAC and SR ryanodine receptor (RyR) during aging, with adverse functional consequences on SR (Ca2+ transients and sparks). Age-dependent alterations in SR Ca2+ transfer to mitochondria could be reproduced in young cardiomyoctes after pharmacological disruption of the connection between both organelles, an intervention that had no effect in old cardiomyocytes or isolated mitochondria.Conclusion: Defective SR-mitochondria communication underlies inefficient Ca2+ exchange between both organelles that could be responsible, at least in part, for inadequate energy demand/supply matching in the aging heart. [ABSTRACT FROM PUBLISHER]

Published
2014
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29. P166 Extracellular RNA in cardiac ischemia/reperfusion injury: prevention of heart failure and cell damage by RNase1.

Author

Cabrera-Fuentes, H A, Ruiz-Meana, M, Kostin, S, Lecour, S, Hausenloy, DJ, Garcia-Dorado, DJ, Schluter, KD, and Preissner, KT

Subjects
*RNA, *REPERFUSION injury, *HEART failure, *RIBONUCLEASES, *MORTALITY, *MYOCARDIAL infarction
Abstract

Despite optimal therapy, the morbidity and mortality of patients presenting with an acute myocardial infarction (MI) remain significant. Extracellular RNA (eRNA), exposed after cell damage, serves as cofactor for coagulation proteases and cytokines thereby promoting their procoagulant and proinflammatory functions in vivo. Following myocardial ischemia/reperfusion (I/R) in mice or I/R induced in the isolated Langendorff heart, increased eRNA levels were found together with cell injury markers. Likewise, eRNA was released from cardiomyocytes under hypoxia and subsequently induced tumor-necrosis-factor-a (TNF-α) liberation by activation of TNF-α converting enzyme (TACE) and provoked cardiomyocyte death. Conversely, TNF-a promoted eRNA release especially under hypoxia, feeding a vicious cell damaging cycle during I/R. Administration of RNase1 or TAPI (TACE-inhibitor) prevented cell death and myocardial infarction. Likewise, RNase1 significantly reduced I/R-mediated energy exhaustion, opening of mitochondrial permeability transition pores (mPTP) as well as oxidative damage in cardiomyocytes. Together, RNase1 as well as inhibition of TACE provide novel therapeutic regimen to interfere with the adverse eRNA-TNF-a interplay and significantly reduce or prevent the pathological outcome of ischemic heart injury. [ABSTRACT FROM PUBLISHER]

Published
2014
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30. P375 Ischemic postconditioning delays recovery of passive myocardial electrical properties independently of connexin 43 expression.

Author

Rodriguez-Sinovas, A, Diez, E, Sanchez, JA, Ruiz-Meana, M, and Garcia-Dorado, D

Subjects
CORONARY disease, MYOCARDIAL infarction risk factors, ELECTRIC properties of hearts, CONNEXINS, GENE expression, MYOCARDIAL revascularization
Abstract

Background: Ventricular arrhythmias are a common clinical manifestation in patients with acute myocardial infarction submitted to coronary revascularizaton. Reperfusion arrhythmias have been associated with successful myocardial reperfusion during thrombolytic therapy, but they have been also suggested to be a marker of large infarct size and worse prognosis. Ischemic postconditioning (PostC) has been shown to reduce the incidence of reperfusion arrhythmias. However, the mechanisms involved in the antiarrhythmic effects of ischemic PostC are not well known. The aims of this study were (1) to analyze the electrophysiologycal effects of ischemic PostC on passive myocardial electrical properties, as a surrogate of gap junctional communication, in isolated rat hearts, and (2) to assess the involvement of connexin 43 (Cx43) in these effects, using isolated hearts from wild-type mice and from mice devoid of connexin 43.Methods and results: Isolated rat hearts were submitted to 20 min of global ischemia followed by 25 min of reperfusion. Myocardial electrical impedance (tissue resistivity and phase angle) was assessed using a four-electrode probe, placed in the left ventricular free wall, at 7 kHz. Global ischemia induced a marked rise in resistivity and a decrease in phase angle (p≤0.05). Ischemic PostC (6 cycles of 10 seconds of reperfusion/ischemia, n=7), applied at the onset of reperfusion, slowed and delayed, by about 4 min, recovery of tissue resistivity as compared with recovery in control hearts. To analyze the involvement of Cx43 in these changes, isolated hearts from two Cx43-defficient mice (Cx43KI32 mice, in which the coding region for Cx43 is replaced by that of Cx32, and a inducible knock-out model, in which a marked reduction in Cx43 expression is achieved after 4-hydroxytamoxifen administration) were submitted to 30 min of global ischemia followed by reperfusion. Hearts from wild-type animals and from both homozygous Cx43KI32 mice (n=6-8) and Cx43Cre-ER(T)/fl mice (n=7-8), were protected against infarction by ischemic PostC (6 cycles of 10 seconds of reperfusion/ischemia). Similar to findings in isolated rat and mice wild-type hearts, ischemic PostC still delayed recovery of tissue resisitvity (about 3 min) in hearts from Cx43-defficient animals.Conclusions: Ischemic PostC delays recovery of tissue resistivity during reperfusion, but this effect is indepenent of Cx43 expression.. The mechanisms of the antiarrhythmic effect of ischemic postconditioning remain elusive. [ABSTRACT FROM AUTHOR]

Published
2014
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31. P141 Prevention of microtubule disruption with paclitaxel does not protect against infarction in isolated rat hearts.

Author

Rodriguez-Sinovas, A, Abad, E, Sanchez, JA, Fernandez-Sanz, C, Inserte, J, Ruiz-Meana, M, and Garcia-Dorado, D

Subjects
MICROTUBULES, PACLITAXEL, MYOCARDIAL infarction, EUKARYOTES, CYTOSKELETON, LABORATORY rats
Abstract

Background: Microtubules are highly dynamic polymers present in eukaryote cells that are essential components of cell cytoskeleton. They play an important role in intracellular transport, in maintaining organelle organization and function, and in transmitting mechanical forces within the myocardium. However, this intracellular network becomes disrupted during myocardial ischemia/reperfusion, and it has been proposed that microtubule disruption is an early sign of irreversible ischemic injury, and that prevention of microtubule disruption during ischemia-reperfusion could be beneficial. In this study we aimed to assess the effects of prevention of microtubule disruption with paclitaxel on ischemia/reperfusion injury in both isolated rat cardiomyocytes and isolated, Langendorff-perfused, rat hearts.Methods and results: Isolated rat cardiomyocytes were submitted to normoxia (1h), or to 50 min of anoxia (pH 6.4, 0% O2, 37° C) and 15 min reoxygenation, without or with treatment during anoxia with the microtubule stabilizer paclitaxel (10 μM) or the inhibitor of microtubule polymerization colchicine (5 μM). The condition of microtubule network was assessed by immunofluorescence detection of α-tubulin. Anoxia/reoxygenation leads to disruption of the microtubule network before the onset of ischemic contracture (650±21 vs. 328±11 arbitrary units of fluorescence (auf), p≤0.05). Paclitaxel attenuated both microtubule disruption (377±15 auf, p≤0.05 vs. anoxia/reoxygenation) and the incidence of hypercontracture (31±7 % vs. 56±8 % in anoxia/reoxygenation, p≤0.05) induced by anoxia/reoxygenation, whereas treatment with colchicine mimicked the effects of anoxia/reoxygenation (fluorescence: 188±16 auf, p≤0.01 vs. anoxia/reoxygenation; hypercontracture: 65±7 %). In isolated rat hearts under normoxic conditions, paclitaxel induced a concentration-dependent increase in perfusion pressure and a decrease in heart rate and left ventricular developed pressure. Despite protection against cell hypercontracture, paclitaxel pretreatment did not modify infarct size (60.37±2.27 % in control hearts vs. 58.75±10.25, 55.44±10.32 and 50.06±10.14 % in hearts pretreated with 10-6, 3 10-6 and 10-5 M, of paclitaxel respectively), LDH release or functional recovery after 60 min of global ischemia and reperfusion in isolated rat hearts.Conclusions: Microtubule stabilization with paclitaxel reduces hypercontracture in isolated rat cardiomyocytes but does not protect against infarction in isolated rat hearts. [ABSTRACT FROM AUTHOR]

Published
2014
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32. Spontaneous reperfusion enhances succinate concentration in peripheral blood from stemi patients but its levels does not correlate with myocardial infarct size or area at risk

Author

Marta Consegal, Ignasi Barba, Bruno García del Blanco, Imanol Otaegui, José F. Rodríguez-Palomares, Gerard Martí, Bernat Serra, Neus Bellera, Manuel Ojeda-Ramos, Filipa Valente, Maria Ángeles Carmona, Elisabet Miró-Casas, Antonia Sambola, Rosa María Lidón, Jordi Bañeras, José Antonio Barrabés, Cristina Rodríguez, Begoña Benito, Marisol Ruiz-Meana, Javier Inserte, Ignacio Ferreira-González, Antonio Rodríguez-Sinovas, Institut Català de la Salut, [Consegal M, Benito B, Ruiz-Meana M, Inserte J, Rodríguez-Sinovas A] Grup de Recerca de Malalties Cardiovasculars, Vall d’Hebron Institut de Recerca (VHIR), Barcelona, Spain. Servei de Cardiologia, Vall d’Hebron Hospital Universitari, Barcelona, Spain. Departament de Medicina, Universitat Autònoma de Barcelona, Bellaterra, Spain. Centro de Investigación Biomédica en Red (CIBER) de Enfermedades Cardiovasculares (CIBERCV), Instituto de Salud Carlos III, Madrid, Spain. [Barba I] Grup de Recerca de Malalties Cardiovasculars, Vall d’Hebron Institut de Recerca (VHIR), Barcelona, Spain. Servei de Cardiologia, Vall d’Hebron Hospital Universitari, Barcelona, Spain. Departament de Medicina, Universitat Autònoma de Barcelona, Bellaterra, Spain. Centro de Investigación Biomédica en Red (CIBER) de Enfermedades Cardiovasculares (CIBERCV), Instituto de Salud Carlos III, Madrid, Spain. Faculty of Medicine, University of Vic - Central University of Catalonia (UVicUCC), Vic, Spain. [García Del Blanco B, Otaegui I, Rodríguez-Palomares JF, Martí G, Serra B, Bellera N, Ojeda-Ramos M, Valente F, Carmona MÁ, Miró-Casas E, Sambola A, Lidón RM, Bañeras J, Barrabés JA] Grup de Recerca de Malalties Cardiovasculars, Vall d’Hebron Institut de Recerca (VHIR), Barcelona, Spain. Servei de Cardiologia, Vall d’Hebron Hospital Universitari, Barcelona, Spain. Centro de Investigación Biomédica en Red (CIBER) de Enfermedades Cardiovasculares (CIBERCV), Instituto de Salud Carlos III, Madrid, Spain. [Ferreira-González I] Grup de Recerca de Malalties Cardiovasculars, Vall d’Hebron Institut de Recerca (VHIR), Barcelona, Spain. Servei de Cardiologia, Vall d’Hebron Hospital Universitari, Barcelona, Spain. Departament de Medicina, Universitat Autònoma de Barcelona, Bellaterra, Spain. Centro de Investigación Biomédica en Red (CIBER) de Epidemiología y Salud Pública, CIBERESP, Instituto de Salud Carlos III, Madrid, Spain, and Vall d'Hebron Barcelona Hospital Campus

Subjects
Surgical Procedures, Operative::Cardiovascular Surgical Procedures::Reperfusion [ANALYTICAL, DIAGNOSTIC AND THERAPEUTIC TECHNIQUES, AND EQUIPMENT], Infart de miocardi, Multidisciplinary, Reperfusió (Fisiologia), compuestos orgánicos::ácidos carboxílicos::ácidos acíclicos::ácidos dicarboxílicos::succinatos::ácido succínico [COMPUESTOS QUÍMICOS Y DROGAS], Organic Chemicals::Carboxylic Acids::Acids, Acyclic::Dicarboxylic Acids::Succinates::Succinic Acid [CHEMICALS AND DRUGS], intervenciones quirúrgicas::procedimientos quirúrgicos cardiovasculares::reperfusión [TÉCNICAS Y EQUIPOS ANALÍTICOS, DIAGNÓSTICOS Y TERAPÉUTICOS], enfermedades cardiovasculares::enfermedades cardíacas::isquemia miocárdica::infarto de miocardio [ENFERMEDADES], Cardiovascular Diseases::Heart Diseases::Myocardial Ischemia::Myocardial Infarction [DISEASES]
Abstract

Cardiovascular biology; Diagnostic markers; Prognostic markers Biología cardiovascular; Marcadores de diagnóstico; Marcadores pronósticos Biologia cardiovascular; Marcadors diagnòstics; Marcadors pronòstics Succinate is enhanced during initial reperfusion in blood from the coronary sinus in ST-segment elevation myocardial infarction (STEMI) patients and in pigs submitted to transient coronary occlusion. Succinate levels might have a prognostic value, as they may correlate with edema volume or myocardial infarct size. However, blood from the coronary sinus is not routinely obtained in the CathLab. As succinate might be also increased in peripheral blood, we aimed to investigate whether peripheral plasma concentrations of succinate and other metabolites obtained during coronary revascularization correlate with edema volume or infarct size in STEMI patients. Plasma samples were obtained from peripheral blood within the first 10 min of revascularization in 102 STEMI patients included in the COMBAT-MI trial (initial TIMI 1) and from 9 additional patients with restituted coronary blood flow (TIMI 2). Metabolite concentrations were analyzed by 1H-NMR. Succinate concentration averaged 0.069 ± 0.0073 mmol/L in patients with TIMI flow ≤ 1 and was significantly increased in those with TIMI 2 at admission (0.141 ± 0.058 mmol/L, p

Published
2023

33. Connexin 43 in Mitochondria: What Do We Really Know About Its Function?

Author

Kerstin Boengler, Luc Leybaert, Marisol Ruiz-Meana, Rainer Schulz, Institut Català de la Salut, [Boengler K, Schulz R] Institute of Physiology, Justus-Liebig University, Giessen, Germany. [Leybaert L] Department of Basic and Applied Medical Sciences—Physiology Group, Faculty of Medicine and Health Sciences, Ghent University, Ghent, Belgium. [Ruiz-Meana M] Grup de Recerca en Malalties Cardiovasculars, Vall d’Hebron Institut de Recerca (VHIR), Barcelona, Spain. Vall d’Hebron Hospital Universitari, Barcelona, Spain, and Vall d'Hebron Barcelona Hospital Campus

Subjects
Cor - Fisiologia patològica, connexin, Other subheadings::Other subheadings::/physiopathology [Other subheadings], Otros calificadores::Otros calificadores::/fisiopatología [Otros calificadores], hemichannel, Physiology, ischemia-reperfusion injury, Connexines - Metabolisme, Biology and Life Sciences, Amino Acids, Peptides, and Proteins::Proteins::Membrane Proteins::Membrane Transport Proteins::Connexins::Connexin 43 [CHEMICALS AND DRUGS], Other subheadings::Other subheadings::/metabolism [Other subheadings], enfermedades cardiovasculares::enfermedades cardíacas [ENFERMEDADES], mitochondria, Cardiovascular Diseases::Heart Diseases [DISEASES], preconditioning, Physiology (medical), aminoácidos, péptidos y proteínas::proteínas::proteínas de membranas::proteínas de transporte de membrana::conexinas::conexina 43 [COMPUESTOS QUÍMICOS Y DROGAS], Medicine and Health Sciences, GJA1-20k, Cor - Malalties, Otros calificadores::Otros calificadores::/metabolismo [Otros calificadores]
Abstract

Connexin: Ischemia-reperfusion injury; Mitochondria Conexina; Lesión por isquemia-reperfusión; Mitocondrias Connexina; Lesió per isquèmia-reperfusió; Mitocondris Connexins are known for their ability to mediate cell-cell communication via gap junctions and also form hemichannels that pass ions and molecules over the plasma membrane when open. Connexins have also been detected within mitochondria, with mitochondrial connexin 43 (Cx43) being the best studied to date. In this review, we discuss evidence for Cx43 presence in mitochondria of cell lines, primary cells and organs and summarize data on its localization, import and phosphorylation status. We further highlight the influence of Cx43 on mitochondrial function in terms of respiration, opening of the mitochondrial permeability transition pore and formation of reactive oxygen species, and also address the presence of a truncated form of Cx43 termed Gja1-20k. Finally, the role of mitochondrial Cx43 in pathological conditions, particularly in the heart, is discussed. KB is funded by the German Research Foundation (BO 2955/4-1). LL is supported by the Research Foundation Flanders (FWO) grant numbers G.0527.18N and G040720N. MR-M is supported by the Instituto de Salud Carlos III of the Spanish Ministry of Health (FIS-PI19-01196) and a grant from the Sociedad Española de Cardiología (SEC/FEC-INV- BAS 217003).

Published
2022
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34. Calpains as Potential Therapeutic Targets for Myocardial Hypertrophy

Author

David Aluja, Sara Delgado-Tomás, Marisol Ruiz-Meana, José A. Barrabés, Javier Inserte, Institut Català de la Salut, [Aluja D, Delgado-Tomás S] Grup de Recerca en Malalties Cardiovasculars, Vall d’Hebron Institut de Recerca (VHIR), Barcelona, Spain. Vall d’Hebron Hospital Universitari, Barcelona, Spain. [Ruiz-Meana M, Barrabés JA, Inserte J] Grup de Recerca en Malalties Cardiovasculars, Vall d’Hebron Institut de Recerca (VHIR), Barcelona, Spain. Vall d’Hebron Hospital Universitari, Barcelona, Spain. Centro de Investigación en Red de Enfermedades Cardiovasculares (CIBERCV), 28029 Madrid, Spain, and Vall d'Hebron Barcelona Hospital Campus

Subjects
Heart Failure, Cardiovascular Diseases::Heart Diseases::Heart Failure [DISEASES], Calpain, Organic Chemistry, Calcium-Binding Proteins, Enzims - Ús terapèutic, Otros calificadores::Otros calificadores::/farmacoterapia [Otros calificadores], Cardiomegaly, General Medicine, Other subheadings::Other subheadings::/drug therapy [Other subheadings], enfermedades cardiovasculares::enfermedades cardíacas::insuficiencia cardíaca [ENFERMEDADES], Catalysis, Computer Science Applications, Inorganic Chemistry, Enzymes and Coenzymes::Enzymes::Hydrolases::Peptide Hydrolases::Cysteine Proteases::Cysteine Endopeptidases::Calpain [CHEMICALS AND DRUGS], enzimas y coenzimas::enzimas::hidrolasas::péptido hidrolasas::cisteína proteasas::cisteína endopeptidasas::calpaína [COMPUESTOS QUÍMICOS Y DROGAS], Animals, Physical and Theoretical Chemistry, Insuficiència renal aguda - Tractament, Molecular Biology, Spectroscopy
Abstract

Calpain; Calpastatin; Myocardial hypertrophy Calpaína; Calpastatina; Hipertrofia miocárdica Calpaïna; Calpastatina; Hipertròfia miocàrdica Despite advances in its treatment, heart failure remains a major cause of morbidity and mortality, evidencing an urgent need for novel mechanism-based targets and strategies. Myocardial hypertrophy, caused by a wide variety of chronic stress stimuli, represents an independent risk factor for the development of heart failure, and its prevention constitutes a clinical objective. Recent studies performed in preclinical animal models support the contribution of the Ca2+-dependent cysteine proteases calpains in regulating the hypertrophic process and highlight the feasibility of their long-term inhibition as a pharmacological strategy. In this review, we discuss the existing evidence implicating calpains in the development of cardiac hypertrophy, as well as the latest advances in unraveling the underlying mechanisms. Finally, we provide an updated overview of calpain inhibitors that have been explored in preclinical models of cardiac hypertrophy and the progress made in developing new compounds that may serve for testing the efficacy of calpain inhibition in the treatment of pathological cardiac hypertrophy. This study was funded by the Instituto de Salud Carlos III of the Spanish Ministry of Health FIS-PI20/01681) and the research network CIBERCV (CB16/11/00479).

Published
2022

35. Defective dimerization of FoF1‐ATP synthase secondary to glycation favors mitochondrial energy deficiency in cardiomyocytes during aging

Author

Diana Bou‐Teen, Celia Fernandez‐Sanz, Elisabet Miro‐Casas, Zuzana Nichtova, Elena Bonzon‐Kulichenko, Kelly Casós, Javier Inserte, Antonio Rodriguez‐Sinovas, Begoña Benito, Shey‐Shing Sheu, Jesús Vázquez, Ignacio Ferreira‐González, Marisol Ruiz‐Meana, Instituto de Salud Carlos III, Ministerio de Salud (España), Sociedad Española de Cardiología, Institut Català de la Salut, [Bou-Teen D, Miro-Casas E, Casós K, Inserte J, Rodriguez-Sinovas A, Benito B, Ruiz-Meana M] Grup de Recerca en Malalties Cardiovasculars, Vall d’Hebron Institut de Recerca (VHIR), Barcelona, Spain. Vall d’Hebron Hospital Universitari, Barcelona, Spain. [Fernandez-Sanz C, Sheu SS] Center for Translational Medicine, Department of Medicine, Thomas Jefferson University, Philadelphia, USA. [Nichtova Z] MitoCare Center for Mitochondrial Imaging Research and Diagnostics, Department of Pathology, Anatomy & Cell Biol., Thomas Jefferson University, Philadelphia, USA. [Bonzon-Kulichenko E, Vázquez J] Centro de Investigación Biomédica en Red de Enfermedades Cardiovasculares (CIBER-CV), Madrid, Spain. Cardiovascular Proteomics Laboratory, Centro Nacional de Investigaciones Cardiovasculares Carlos III, Madrid, Spain. [Ferreira-González I] Grup de Recerca en Malalties Cardiovasculars, Vall d’Hebron Institut de Recerca (VHIR), Barcelona, Spain. Vall d’Hebron Hospital Universitari, Barcelona, Spain, and Vall d'Hebron Barcelona Hospital Campus

Subjects
Glycation End Products, Advanced, Aging, Mitochondrial Permeability Transition Pore, Other subheadings::Other subheadings::/metabolism [Other subheadings], Cell Biology, Mitochondrial Proton-Translocating ATPases, Mitochondria, Heart, Mice, Adenosine Triphosphate, Animals, Myocytes, Cardiac, Calcium, Mitocondris - Malalties, Cèl·lules - Envelliment, células::estructuras celulares::espacio intracelular::citoplasma::estructuras citoplasmáticas::orgánulos::mitocondrias::mitocondrias musculares::mitocondrias cardíacas [ANATOMÍA], Dimerization, Cells::Cellular Structures::Intracellular Space::Cytoplasm::Cytoplasmic Structures::Organelles::Mitochondria::Mitochondria, Muscle::Mitochondria, Heart [ANATOMY], Otros calificadores::Otros calificadores::/metabolismo [Otros calificadores]
Abstract

Aging; Dicarbonyl stress; Mitochondria Envelliment; Estrès dicarbonílic; Mitocondris Envejecimiento; Estrés dicarbonílico; Mitocondrias Aged cardiomyocytes develop a mismatch between energy demand and supply, the severity of which determines the onset of heart failure, and become prone to undergo cell death. The FoF1-ATP synthase is the molecular machine that provides >90% of the ATP consumed by healthy cardiomyocytes and is proposed to form the mitochondrial permeability transition pore (mPTP), an energy-dissipating channel involved in cell death. We investigated whether aging alters FoF1-ATP synthase self-assembly, a fundamental biological process involved in mitochondrial cristae morphology and energy efficiency, and the functional consequences this may have. Purified heart mitochondria and cardiomyocytes from aging mice displayed an impaired dimerization of FoF1-ATP synthase (blue native and proximity ligation assay), associated with abnormal mitochondrial cristae tip curvature (TEM). Defective dimerization did not modify the in vitro hydrolase activity of FoF1-ATP synthase but reduced the efficiency of oxidative phosphorylation in intact mitochondria (in which membrane architecture plays a fundamental role) and increased cardiomyocytes’ susceptibility to undergo energy collapse by mPTP. High throughput proteomics and fluorescence immunolabeling identified glycation of 5 subunits of FoF1-ATP synthase as the causative mechanism of the altered dimerization. In vitro induction of FoF1-ATP synthase glycation in H9c2 myoblasts recapitulated the age-related defective FoF1-ATP synthase assembly, reduced the relative contribution of oxidative phosphorylation to cell energy metabolism, and increased mPTP susceptibility. These results identify altered dimerization of FoF1-ATP synthase secondary to enzyme glycation as a novel pathophysiological mechanism involved in mitochondrial cristae remodeling, energy deficiency, and increased vulnerability of cardiomyocytes to undergo mitochondrial failure during aging. This work was supported by the Instituto de Salud Carlos III of the Spanish Ministry of Health (FIS-PI19-01196) and a grant from the Sociedad Española de Cardiología (SEC/FEC-INV-BAS 217003)

Published
2022

36. Cardiac-Specific Overexpression of ERRγ in Mice Induces Severe Heart Dysfunction and Early Lethality

Author

Marc Velilla, Jaime Lasheras, Rafael Simó, Monica Zamora, Marcos Poncelas, Rosario Pardo, Josep A. Villena, Núria Salvatella, Marisol Ruiz-Meana, Institut Català de la Salut, [Lasheras J, Pardo R, Velilla M, Salvatella N] Laboratori de Metabolisme i Obesitat, Vall d’Hebron Hospital Universitari, Barcelona, Spain. Vall d’Hebron Institut de Recerca (VHIR), Barcelona, Spain. Universitat Autònoma de Barcelona, Bellaterra, Spain. [Poncelas M, Ruiz-Meana M] Laboratori de Cardiologia Experimental, Vall d’Hebron Hospital Universitari, Barcelona, Spain. Vall d’Hebron Institut de Recerca (VHIR), Barcelona, Spain. Universitat Autònoma de Barcelona, Bellaterra, Spain. [Simó R] Unitat de Diabetis i Metabolisme, Vall d’Hebron Hospital Universitari, Barcelona, Spain. Vall d’Hebron Institut de Recerca (VHIR), Barcelona, Spain. Universitat Autònoma de Barcelona, Bellaterra, Spain. CIBER on Diabetes and Associated Metabolic Diseases (CIBERDEM), 28029 Madrid, Spain. [Villena JA] Laboratori de Metabolisme i Obesitat, Vall d’Hebron Hospital Universitari, Barcelona, Spain. Vall d’Hebron Institut de Recerca (VHIR), Barcelona, Spain. Universitat Autònoma de Barcelona, Bellaterra, Spain. CIBER on Diabetes and Associated Metabolic Diseases (CIBERDEM), 28029 Madrid, Spain, and Vall d'Hebron Barcelona Hospital Campus

Subjects
0301 basic medicine, Cardiovascular Diseases::Heart Diseases::Cardiomegaly::Cardiomyopathy, Dilated [DISEASES], 030204 cardiovascular system & hematology, células::células musculares::miocitos cardíacos [ANATOMÍA], Mice, 0302 clinical medicine, Fibrosis, Diabetic cardiomyopathy, Medicine, Myocytes, Cardiac, Biology (General), Receptor, Spectroscopy, Otros calificadores::Otros calificadores::/metabolismo [Otros calificadores], cardiac dysfunction, Dilated cardiomyopathy, Other subheadings::Other subheadings::/metabolism [Other subheadings], General Medicine, Computer Science Applications, Cell biology, Chemistry, Receptors, Estrogen, estrogen-related receptors, Cardiac function curve, Cardiomyopathy, Dilated, Programmed cell death, QH301-705.5, enfermedades cardiovasculares::enfermedades cardíacas::cardiomegalia::miocardiopatía dilatada [ENFERMEDADES], Cells::Muscle Cells::Myocytes, Cardiac [ANATOMY], Mice, Transgenic, transgenic mice, Catalysis, Article, Inorganic Chemistry, 03 medical and health sciences, Animals, Physical and Theoretical Chemistry, QD1-999, Molecular Biology, business.industry, Myocardium, Organic Chemistry, medicine.disease, Miocardi - Malalties - Metabolisme, Cor - Metabolisme, Mice, Inbred C57BL, 030104 developmental biology, Nuclear receptor, Heart failure, business
Abstract

Disfunció cardíaca; Receptors relacionats amb estrògens; Ratolins transgènics Disfunción cardíaca; Receptores relacionados con el estrógeno; Ratones transgénicos Cardiac dysfunction; Estrogen-related receptors; Transgenic mice Proper cardiac function depends on the coordinated expression of multiple gene networks related to fuel utilization and mitochondrial ATP production, heart contraction, and ion transport. Key transcriptional regulators that regulate these gene networks have been identified. Among them, estrogen-related receptors (ERRs) have emerged as crucial modulators of cardiac function by regulating cellular metabolism and contraction machinery. Consistent with this role, lack of ERRα or ERRγ results in cardiac derangements that lead to functional maladaptation in response to increased workload. Interestingly, metabolic inflexibility associated with diabetic cardiomyopathy has been recently associated with increased mitochondrial fatty acid oxidation and expression of ERRγ, suggesting that sustained expression of this nuclear receptor could result in a cardiac pathogenic outcome. Here, we describe the generation of mice with cardiac-specific overexpression of ERRγ, which die at young ages due to heart failure. ERRγ transgenic mice show signs of dilated cardiomyopathy associated with cardiomyocyte hypertrophy, increased cell death, and fibrosis. Our results suggest that ERRγ could play a role in mediating cardiac pathogenic responses. Research was funded by “Fundació la Marató de TV3” (# 082610 to JAV) and by Instituto de Salud Carlos III (PI19/00167 to MZ, co-funded by European Regional Development Fund -FEDER- “A way to make Europe”).

Published
2021

37. Citric Acid Cycle Metabolites Predict Infarct Size in Pigs Submitted to Transient Coronary Artery Occlusion and Treated with Succinate Dehydrogenase Inhibitors or Remote Ischemic Perconditioning

Author

Begoña Benito, Marisol Ruiz-Meana, Javier Inserte, Norberto Núñez, Marta Consegal, Ignacio Ferreira-González, Antonio Rodríguez-Sinovas, Ignasi Barba, Institut Català de la Salut, [Consegal M, Benito B, Ruiz-Meana M, Inserte J, Rodríguez-Sinovas A] Grup de Recerca en Malalties Cardiovasculars, Servei de Cardiologia, Vall d’Hebron Institut de Recerca (VHIR), Barcelona, Spain. Vall d’Hebron Hospital Universitari, Barcelona, Spain. Departament de Medicina, Universitat Autònoma de Barcelona, Bellaterra, Spain. Centro de Investigación Biomédica en Red (CIBER) de Enfermedades Cardiovasculares (CIBERCV), Instituto de Salud Carlos III, 28029 Madrid, Spain. [Núñez N] Unitat d'Alta Tecnologia, Vall d’Hebron Institut de Recerca (VHIR), Barcelona, Spain. Vall d’Hebron Hospital Universitari, Barcelona, Spain. [Barba I] Grup de Recerca en Malalties Cardiovasculars, Servei de Cardiologia, Vall d’Hebron Institut de Recerca (VHIR), Barcelona, Spain. Vall d’Hebron Hospital Universitari, Barcelona, Spain. Departament de Medicina, Universitat Autònoma de Barcelona, Bellaterra, Spain. Centro de Investigación Biomédica en Red (CIBER) de Enfermedades Cardiovasculares (CIBERCV), Instituto de Salud Carlos III, 28029 Madrid, Spain. Faculty of Medicine, University of Vic-Central University of Catalonia (UVicUCC), Can Baumann. Ctra. de Roda, 70, 08500 Vic, Spain. [Ferreira-González I] Grup de Recerca en Malalties Cardiovasculars, Servei de Cardiologia, Vall d’Hebron Institut de Recerca (VHIR), Barcelona, Spain. Vall d’Hebron Hospital Universitari, Barcelona, Spain. Departament de Medicina, Universitat Autònoma de Barcelona, Bellaterra, Spain. Centro de Investigación Biomédica en Red (CIBER) de Epidemiología y Salud Pública (CIBERESP), Instituto de Salud Carlos III, 28029 Madrid, Spain, and Vall d'Hebron Barcelona Hospital Campus

Subjects
0301 basic medicine, Swine, Endogeny, 030204 cardiovascular system & hematology, Pharmacology, ischemia-reperfusion, Cardiovascular Diseases::Heart Diseases::Myocardial Ischemia::Myocardial Infarction [DISEASES], chemistry.chemical_compound, 0302 clinical medicine, hemic and lymphatic diseases, Dicarboxylic Acids, Myocardial infarction, Biology (General), Enzyme Inhibitors, Ischemic Preconditioning, Spectroscopy, remote ischemic conditioning, biology, Àcid cítric - Metabolisme, Chemistry, Succinate dehydrogenase, Ischemia-reperfusion, metabolismo::metabolismo energético::metabolismo::ciclo del ácido cítrico [FENÓMENOS Y PROCESOS], Remote ischemic conditioning, Heart, General Medicine, enfermedades cardiovasculares::enfermedades cardíacas::isquemia miocárdica::infarto de miocardio [ENFERMEDADES], Computer Science Applications, Malonate, myocardial infarction, Other subheadings::Other subheadings::/administration & dosage [Other subheadings], sustancias macromoleculares::complejos multiproteicos::complejos multienzimáticos::succinato citocromo c oxidorreductasa::complejo II de transporte de electrones::succinato deshidrogenasa [COMPUESTOS QUÍMICOS Y DROGAS], QH301-705.5, Sodium, Citric Acid Cycle, chemistry.chemical_element, Catalysis, Great cardiac vein, Article, Inorganic Chemistry, 03 medical and health sciences, Metabolism::Energy Metabolism::Metabolism::Citric Acid Cycle [PHENOMENA AND PROCESSES], medicine, Animals, Physical and Theoretical Chemistry, Molecular Biology, QD1-999, Macromolecular Substances::Multiprotein Complexes::Multienzyme Complexes::Succinate Cytochrome c Oxidoreductase::Electron Transport Complex II::Succinate Dehydrogenase [CHEMICALS AND DRUGS], Otros calificadores::Otros calificadores::/administración & dosificación [Otros calificadores], Myocardium, Organic Chemistry, medicine.disease, succinate dehydrogenase, malonate, Citric acid cycle, Infart de miocardi, 030104 developmental biology, Coronary Occlusion, Inhibidors enzimàtics, Coronary occlusion, biology.protein, Biomarkers
Abstract

Succinate dehydrogenase (SDH) inhibition with malonate during reperfusion reduced myocardial infarction in animals, whereas its endogenous substrate, succinate, is detected in plasma from STEMI patients. We investigated whether protection by SDH inhibition is additive to that of remote ischemic perconditioning (RIC) in pigs submitted to transient coronary artery occlusion, and whether protective maneuvers influence plasma levels of citric acid cycle metabolites. Forty pigs were submitted to 40 min coronary occlusion and reperfusion, and allocated to four groups (controls, sodium malonate 10 mmol/L, RIC, and malonate + RIC). Plasma was obtained from femoral and great cardiac veins and analyzed by LC-MS/MS. Malonate, RIC, and malonate + RIC reduced infarct size (24.67 ± 5.98, 25.29 ± 3.92 and 29.83 ± 4.62% vs. 46.47 ± 4.49% in controls, p &lt, 0.05), but no additive effects were detected. Enhanced concentrations of succinate, fumarate, malate and citrate were observed in controls during initial reperfusion in the great cardiac vein, and most were reduced by cardioprotective maneuvers. Concentrations of succinate, fumarate, and malate significantly correlated with infarct size. In conclusion, despite the combination of SDH inhibition during reperfusion and RIC did not result in additive protection, plasma concentrations of selected citric acid cycle metabolites are attenuated by protective maneuvers, correlate with irreversible injury, and might become a prognosis tool in STEMI patients.

Published
2021

38. IMproving Preclinical Assessment of Cardioprotective Therapies (IMPACT) criteria: guidelines of the EU-CARDIOPROTECTION COST Action

Author

Lecour, Sandrine, Andreadou, Ioanna, Bøtker, Hans Erik, Davidson, Sean M., Heusch, Gerd, Ruiz-Meana, Marisol, Schulz, Rainer, Zuurbier, Coert J., Ferdinandy, Péter, Hausenloy, Derek J., Adamovski, Pavle, Batirel, Saime, Barteková, Monika, Bertrand, Luc, Beauloye, Christophe, Biedermann, David, Borutaite, Vilmante, Chlopicki, Stefan, Dambrova, Maija, Devaux, Yvan, Di Lisa, Fabio, Djuric, Dragan, Erlinge, David, Falcao-Pires, Ines, Galatou, Eleftheria, Garcia-Sosa, Alfonso, Girao, Henrique, Giricz, Zoltan, Gyongyosi, Mariann, Healy, Donagh, Jakovljevic, Vladimir, Jovanic, Jelena, Kararigas, George, Kerkal, Risto, Kolar, Frantisek, Kwak, Brenda, Leszek, Przemysław, Liepinsh, Edgars, Lonborg, Jacob, Longnus, Sarah, Marinovic, Jasna, Muntean, Danina Mirela, Nezic, Lana, Ovize, Michel, Pagliaro, Pasquale, Da Costa Gomes, Clarissa Pedrosa, Pernow, John, Persidis, Andreas, Pischke, Søren Erik, Podesser, Bruno, Potočnjak, Ines, Prunier, Fabrice, Ravingerova, Tanya, Serban, Alina, Slagsvold, Katrine, van Royen, Niels, Turan, Belma, Vendelin, Marko, Walsh, Stewart, Zidar, Nace, Yellon, Derek, Institut Català de la Salut, [Lecour S] Department of Medicine, Hatter Institute for Cardiovascular Research in Africa, University of Cape Town, Cape Town, South Africa. [Andreadou I] Laboratory of Pharmacology, Faculty of Pharmacy, National and Kapodistrian University of Athens, Athens, Greece. [Bøtker HE] Department of Cardiology, Aarhus University Hospital, Aarhus N, Denmark. [Davidson SM] The Hatter Cardiovascular Institute, University College London, London, UK. [Heusch G] Institute for Pathophysiology, West German Heart and Vascular Center, University of Duisburg-Essen, Essen, Germany. [Ruiz-Meana M] Grup de Recerca en Malalties Cardiovasculars, Vall d’Hebron Institut de Recerca (VHIR), Barcelona, Spain. Vall d’Hebron Hospital Universitari, Barcelona, Spain, and Vall d'Hebron Barcelona Hospital Campus

Subjects
Otros calificadores::Otros calificadores::/prevención & control [Otros calificadores], medicine.medical_specialty, enfermedades cardiovasculares::enfermedades vasculares::daño por reperfusión [ENFERMEDADES], genetic structures, Physiology, Medizin, Myocardial Infarction, Ischemia, Psychological intervention, Infarction, 610 Medicine & health, Drug development, Cardioprotection, Cardiovascular Diseases::Heart Diseases::Myocardial Ischemia::Myocardial Infarction [DISEASES], Reperfusion, Other subheadings::Other subheadings::/prevention & control [Other subheadings], Physiology (medical), medicine, Animals, Humans, Myocardial infarction, Cardiovascular Diseases::Vascular Diseases::Reperfusion Injury [DISEASES], Intensive care medicine, Practical Guideline, Heart Failure, business.industry, Vascular damage Radboud Institute for Molecular Life Sciences [Radboudumc 16], Reperfusió miocardíaca, Cor - Malalties - Prevenció, medicine.disease, enfermedades cardiovasculares::enfermedades cardíacas::isquemia miocárdica::infarto de miocardio [ENFERMEDADES], Cor - Malalties - Tractament, Reperfusion Injury, Heart failure, Cardiology and Cardiovascular Medicine, business, Reperfusion injury
Abstract

Cardioprotection; Drug development; Infarction Cardioprotección; Desarrollo de fármacos; Infarto Cardioprotecció; Desenvolupament de fàrmacs; Infart Acute myocardial infarction (AMI) and the heart failure (HF) which may follow are among the leading causes of death and disability worldwide. As such, new therapeutic interventions are still needed to protect the heart against acute ischemia/reperfusion injury to reduce myocardial infarct size and prevent the onset of HF in patients presenting with AMI. However, the clinical translation of cardioprotective interventions that have proven to be beneficial in preclinical animal studies, has been challenging. One likely major reason for this failure to translate cardioprotection into patient benefit is the lack of rigorous and systematic in vivo preclinical assessment of the efficacy of promising cardioprotective interventions prior to their clinical evaluation. To address this, we propose an in vivo set of step-by-step criteria for IMproving Preclinical Assessment of Cardioprotective Therapies (‘IMPACT’), for investigators to consider adopting before embarking on clinical studies, the aim of which is to improve the likelihood of translating novel cardioprotective interventions into the clinical setting for patient benefit. This article is based on the work from COST Action EU-CARDIOPROTECTION CA16225 supported by COST (European Cooperation in Science and Technology). DJH is supported by the Duke-National University Singapore Medical School, Singapore Ministry of Health’s National Medical Research Council under its Clinician Scientist-Senior Investigator scheme (NMRC/CSA-SI/0011/2017) and Collaborative Centre Grant scheme (NMRC/CGAug16C006). SL is supported by grants from the South African Department of Science and Technology and the South African National Research Foundation. SMD is supported by grants from the British Heart Foundation (PG/19/51/34493 and PG/16/85/32471). GH is supported by the German Research Foundation (SFB 1116 B8). MRM is supported by the Spanish Institute of Health Carlos III (FIS PI19/01196 and CIBER-CV). RS is supported by Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) [Project number 268555672—SFB 1213, Project B05]. PF is supported by the National Research, Development and Innovation Office of Hungary (Research Excellence Program—TKP, National Heart Program NVKP 16-1-2016-0017) and by the Higher Education Institutional Excellence Program of the Ministry of Human Capacities in Hungary, within the framework of the Therapeutic Development thematic program of the Semmelweis University.

Published
2021

39. Cardiac fibroblasts display endurance to ischemia, high ROS control and elevated respiration regulated by the JAK2/STAT pathway

Author

Marta Llovera, Marisol Ruiz-Meana, Andrea Irazoki, Carlos Lana, Javier Inserte, Manuel Portero-Otin, Juan G. Valero, Aida Beà, Guillermo López-Lluch, Antonio Zorzano, Daniel Sanchis, Patricia Pérez-Galán, Ministerio de Economía y Competitividad (España), Ministerio de Ciencia, Innovación y Universidades (España), Agencia Estatal de Investigación (España), Fundació La Marató de TV3, Diputació de Lleida, Generalitat de Catalunya, Instituto de Salud Carlos III, Centres de Recerca de Catalunya, Institut Català de la Salut, [Beà A, Lana C] Cell Signaling & Apoptosis Group, Institut de Recerca Biomedica de Lleida (IRBLleida), Universitat de Lleida, Spain. [Valero JG] Department of Hematology-Oncology, Institut d’Investigacions Biomediques August Pi i Sunyer (IDIBAPS), Barcelona, Spain. Centro de Investigacion Biomédica en Red-Oncología (CIBERONC), Barcelona, Spain. [Irazoki A] Departament de Bioquímica i Biomedicina Molecular, Facultat de Biologia, Institute for Research in Biomedicine (IRB Barcelona), Barcelona Institute of Science and Technology (BIST), Centro de Investigación Biomédica en Red Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Universitat de Barcelona, Spain. [López-Lluch G] Andalusian Center of Developmental Biology, Pablo de Olavide University, Sevilla, Spain. Centro de Investigación Biomédica en Red Enfermedades Raras (CIBERER), Sevilla, Spain. [Portero-Otín M] Department of Experimental Medicine, IRBLleida, University of Lleida, Lleida, Spain. [Inserte J, Ruiz-Meana M] Laboratori de Cardiologia Experimental, Vall d’Hebron Hospital Universitari, Barcelona, Spain. Vall d’Hebron Institut de Recerca (VHIR), Barcelona, Spain. Universitat Autònoma de Barcelona, Spain. Centro de Investigación Biomédica en Red-CV (CIBER-CV), Barcelona, Spain, and Vall d'Hebron Barcelona Hospital Campus

Subjects
STAT3 Transcription Factor, Cellular respiration, Survival, Cardiac fibrosis, Sistema cardiovascular - Malalties, Cardiac fibroblast, Biochemistry, Antioxidants, Ischemia, medicine, Animals, STAT3, Molecular Biology, STAT5, enfermedades cardiovasculares [ENFERMEDADES], biology, Cardiovascular Diseases [DISEASES], Chemistry, Respiration, JAK-STAT signaling pathway, ROS, Cell Biology, Fibroblasts, Janus Kinase 2, medicine.disease, JAK/STAT, Cell biology, Rats, Proto-Oncogene Proteins c-bcl-2, biology.protein, STAT protein, Signal transduction, Janus kinase, Reactive Oxygen Species, Signal Transduction
Abstract

Cardiovascular diseases are the leading cause of death globally and more than four out of five cases are due to ischemic events. Cardiac fibroblasts (CF) contribute to normal heart development and function, and produce the post-ischemic scar. Here, we characterize the biochemical and functional aspects related to CF endurance to ischemia-like conditions. Expression data mining showed that cultured human CF (HCF) express more BCL2 than pulmonary and dermal fibroblasts. In addition, gene set enrichment analysis showed overrepresentation of genes involved in the response to hypoxia and oxidative stress, respiration and Janus kinase (JAK)/Signal transducer and Activator of Transcription (STAT) signaling pathways in HCF. BCL2 sustained survival and proliferation of cultured rat CF, which also had higher respiration capacity and reactive oxygen species (ROS) production than pulmonary and dermal fibroblasts. This was associated with higher expression of the electron transport chain (ETC) and antioxidant enzymes. CF had high phosphorylation of JAK2 and its effectors STAT3 and STAT5, and their inhibition reduced viability and respiration, impaired ROS control and reduced the expression of BCL2, ETC complexes and antioxidant enzymes. Together, our results identify molecular and biochemical mechanisms conferring survival advantage to experimental ischemia in CF and show their control by the JAK2/STAT signaling pathway. The presented data point to potential targets for the regulation of cardiac fibrosis and also open the possibility of a general mechanism by which somatic cells required to acutely respond to ischemia are constitutively adapted to survive it., This research was funded by Ministerio de Ciencia e Innovación (MICINN), Gobierno de España, grant numbers SAF2013-44942-R and PID2019-104509RB-I00 to DS; Fundació La Marató TV3, grant number 20153810 to D.S; A.B. holds a contract from Fundació La Marató TV3 and IRBLleida/Diputació de Lleida; Generalitat de Catalunya, (AGAUR) grant number 2017SGR996 to DS; PP-G Laboratory support was obtained through research grants from MICINN (SAF2017/88275R) and CIBERONC (CB16/12/00334); JI and MR-M Laboratory support was obtained from Instituto de Salud Carlos III (ISCIII-FIS) grant PI19-01196; AZ Laboratory support was obtained through research grants from MICINN (PID2019-106209RB-I00), and the Generalitat de Catalunya, (AGAUR) grant number 2017SGR1015. AZ is a recipient of an ICREA ‘Academia’ Award (Generalitat de Catalunya). We gratefully acknowledge institutional funding from the MINECO through the Centres of Excellence Severo Ochoa Award, and from the CERCA Programme of the Generalitat de Catalunya.

Published
2021

40. Implications of Iron Deficiency in STEMI Patients and in a Murine Model of Myocardial Infarction

Author

Jordi Bañeras, Filipa Valente, Ignacio Ferreira-González, Imanol Otaegui, Ana Sánchez, Laura Castellote, Begoña Benito, Agnès Rafecas, José A. Barrabés, Javier Inserte, José Rodríguez-Palomares, Antonio Rodríguez-Sinovas, Victor Pineda, Elisabet Miró-Casas, Sara Delgado-Tomas, David Beneítez, Rosa-Maria Lidón, Irene Buera, Laia Milà, Antonia Sambola, David Aluja, Marisol Ruiz-Meana, Institut Català de la Salut, [Inserte J, Barrabés JA, Aluja D, Otaegui I, Bañeras J, Sánchez A, Rodríguez-Palomares JF, Miró-Casas E, Milà L, Lidón RM, Sambola A, Valente F, Rafecas A, Ruiz-Meana M, Rodríguez-Sinovas A, Benito B, Buera I, Delgado-Tomás S, Ferreira-González I] Servei de Cardiologia, Vall d’Hebron Hospital Universitari, Barcelona, Spain. Vall d’Hebron Institut de Recerca (VHIR), Barcelona, Spain. Universitat Autònoma de Barcelona, Bellaterra, Spain. Centro de Investigación en Red de Enfermedades Cardiovasculares (CIBERCV), Madrid, Spain. [Castellote L] Servei de Bioquímica, Vall d’Hebron Hospital Universitari, Barcelona, Spain. [Beneítez D] Servei d’Hematologia, Vall d’Hebron Hospital Universitari, Barcelona, Spain. Vall d’Hebron Institute of Oncology (VHIO), Barcelona, Spain, and Vall d'Hebron Barcelona Hospital Campus

Subjects
medicine.medical_treatment, myocardial reperfusion, intervenciones quirúrgicas::intervenciones quirúrgicas::procedimientos quirúrgicos mínimamente invasivos::procedimientos endovasculares::cirugía coronaria percutánea [TÉCNICAS Y EQUIPOS ANALÍTICOS, DIAGNÓSTICOS Y TERAPÉUTICOS], Otros calificadores::Otros calificadores::/efectos adversos [Otros calificadores], Cardiovascular Diseases::Heart Diseases::Myocardial Ischemia::Myocardial Infarction [DISEASES], iron deficiency, CMR, cardiac magnetic resonance, enfermedades hematológicas y linfáticas::enfermedades hematológicas::anemia::anemia hipocrómica::anemia ferropénica [ENFERMEDADES], ID, iron deficiency, Myocardial infarction, sGC, soluble guanylyl cyclase, Malalties coronàries - Cirurgia - Complicacions, medicine.diagnostic_test, CK-MB, creatine kinase-myocardial band, eNOS, endothelial nitric oxide synthase, Iron deficiency, enfermedades cardiovasculares::enfermedades cardíacas::isquemia miocárdica::infarto de miocardio [ENFERMEDADES], Surgical Procedures, Operative::Surgical Procedures, Operative::Minimally Invasive Surgical Procedures::Endovascular Procedures::Percutaneous Coronary Intervention [ANALYTICAL, DIAGNOSTIC AND THERAPEUTIC TECHNIQUES, AND EQUIPMENT], Sgc, soluble guanylyl cyclase, Cardiology, cardiovascular system, iNOS, inducible nitric oxide synthase, Infart de miocardi - Imatgeria, Cardiology and Cardiovascular Medicine, STEMI, ST-segment elevation acute myocardial infarction, soluble guanylate cyclase, medicine.medical_specialty, Ischemia, acute myocardial infarction, Acute myocardial infarction, MVO, microvascular obstruction, Hemic and Lymphatic Diseases::Hematologic Diseases::Anemia::Anemia, Hypochromic::Anemia, Iron-Deficiency [DISEASES], Myocardial reperfusion, Enos, endothelial nitric oxide synthase, Cardiac magnetic resonance imaging, Clinical Research, Internal medicine, STIR, short tau inversion recovery, Other subheadings::Other subheadings::/adverse effects [Other subheadings], medicine, Soluble guanylate cyclase, HSP90, heat-shock protein 90, cardiovascular diseases, Ventricular remodeling, LV, left ventricular, endothelial nitric oxide synthase, Dèficit de ferro, business.industry, Percutaneous coronary intervention, medicine.disease, Coronary occlusion, Inos, inducible nitric oxide synthase, PKG, protein kinase G, Endothelial nitric oxide synthase, business, cGMP-dependent protein kinase, VASP, vasodilator-stimulated phosphoprotein
Abstract

Visual Abstract, Highlights • In patients with STEMI treated with primary percutaneous coronary intervention, iron deficiency is associated with larger infarcts, more extensive microvascular obstruction, and a higher frequency of adverse left ventricular remodeling. • An iron-deficient diet reduces the tolerance to ischemia/reperfusion in mice at least in part by interfering with the cardioprotective pathway eNOS/soluble guanylate cyclase/protein kinase G. • An iron-deficient diet reduces eNOS activity by increasing oxidative/nitrosative stress and its proteasome-dependent degradation. • Not only iron excess but also iron deficiency may have deleterious effects in the context of acute myocardial ischemia., Summary In patients with a first anterior ST-segment elevation myocardial infarction treated with primary percutaneous coronary intervention, iron deficiency (ID) was associated with larger infarcts, more extensive microvascular obstruction, and higher frequency of adverse left ventricular remodeling as assessed by cardiac magnetic resonance imaging. In mice, an ID diet reduced the activity of the endothelial nitric oxide synthase/soluble guanylate cyclase/protein kinase G pathway in association with oxidative/nitrosative stress and increased infarct size after transient coronary occlusion. Iron supplementation or administration of an sGC activator before ischemia prevented the effects of the ID diet in mice. Not only iron excess, but also ID, may have deleterious effects in the setting of ischemia and reperfusion.

Published
2021

41. Long-Term Protective Effects of Succinate Dehydrogenase Inhibition during Reperfusion with Malonate on Post-Infarction Left Ventricular Scar and Remodeling in Mice.

Author

Valls-Lacalle L, Consegal M, Ganse FG, Yáñez-Bisbe L, Pastor J, Ruiz-Meana M, Inserte J, Benito B, Ferreira-González I, and Rodríguez-Sinovas A

Subjects
Animals, Mice, Male, Cicatrix pathology, Cicatrix drug therapy, Mice, Inbred C57BL, Malonates pharmacology, Myocardial Infarction drug therapy, Myocardial Infarction pathology, Succinate Dehydrogenase metabolism, Succinate Dehydrogenase antagonists & inhibitors, Ventricular Remodeling drug effects, Myocardial Reperfusion Injury drug therapy, Myocardial Reperfusion Injury pathology
Abstract

Succinate dehydrogenase inhibition with malonate during initial reperfusion reduces myocardial infarct size in both isolated mouse hearts subjected to global ischemia and in in situ pig hearts subjected to transient coronary ligature. However, the long-term effects of acute malonate treatment are unknown. Here, we investigated whether the protective effects of succinate dehydrogenase inhibition extend to a reduction in scar size and adverse left ventricular remodeling 28 days after myocardial infarction. Initially, ten wild-type mice were subjected to 45 min of left anterior descending coronary artery (LAD) occlusion, followed by 24 h of reperfusion, and were infused during the first 15 min of reperfusion with saline with or without disodium malonate (10 mg/kg/min, 120 μL/kg/min). Malonate-treated mice depicted a significant reduction in infarct size (15.47 ± 3.40% of area at risk vs. 29.34 ± 4.44% in control animals, p < 0.05), assessed using triphenyltetrazolium chloride. Additional animals were then subjected to a 45 min LAD ligature, followed by 28 days of reperfusion. Treatment with a single dose of malonate during the first 15 min of reperfusion induced a significant reduction in scar area, measured using Picrosirius Red staining (11.94 ± 1.70% of left ventricular area (n = 5) vs. 23.25 ± 2.67% (n = 9), p < 0.05), an effect associated with improved ejection fraction 28 days after infarction, as determined using echocardiography, and an attenuated enhancement in expression of the pro-inflammatory and fibrotic markers NF-κB and Smad2/3 in remote myocardium. In conclusion, a reversible inhibition of succinate dehydrogenase with a single dose of malonate at the onset of reperfusion has long-term protective effects in mice subjected to transient coronary occlusion., Competing Interests: The authors declare no conflicts of interest.

Published
2024
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42. TRPV4 Channels Promote Pathological, but Not Physiological, Cardiac Remodeling through the Activation of Calcineurin/NFAT and TRPC6.

Author

Yáñez-Bisbe L, Moya M, Rodríguez-Sinovas A, Ruiz-Meana M, Inserte J, Tajes M, Batlle M, Guasch E, Mas-Stachurska A, Miró E, Rivas N, Ferreira González I, Garcia-Elias A, and Benito B

Subjects
Animals, Mice, Cells, Cultured, Fibrosis, Isoproterenol, Mice, Transgenic, Myocytes, Cardiac metabolism, NFATC Transcription Factors genetics, NFATC Transcription Factors metabolism, TRPC6 Cation Channel genetics, TRPC6 Cation Channel metabolism, Calcineurin metabolism, Heart Failure metabolism, TRPV Cation Channels genetics, TRPV Cation Channels metabolism, Ventricular Remodeling genetics
Abstract

TRPV4 channels, which respond to mechanical activation by permeating Ca 2+ into the cell, may play a pivotal role in cardiac remodeling during cardiac overload. Our study aimed to investigate TRPV4 involvement in pathological and physiological remodeling through Ca 2+ -dependent signaling. TRPV4 expression was assessed in heart failure (HF) models, induced by isoproterenol infusion or transverse aortic constriction, and in exercise-induced adaptive remodeling models. The impact of genetic TRPV4 inhibition on HF was studied by echocardiography, histology, gene and protein analysis, arrhythmia inducibility, Ca 2+ dynamics, calcineurin (CN) activity, and NFAT nuclear translocation. TRPV4 expression exclusively increased in HF models, strongly correlating with fibrosis. Isoproterenol-administered transgenic TRPV4-/- mice did not exhibit HF features. Cardiac fibroblasts (CFb) from TRPV4+/+ animals, compared to TRPV4-/-, displayed significant TRPV4 overexpression, elevated Ca 2+ influx, and enhanced CN/NFATc3 pathway activation. TRPC6 expression paralleled that of TRPV4 in all models, with no increase in TRPV4-/- mice. In cultured CFb, the activation of TRPV4 by GSK1016790A increased TRPC6 expression, which led to enhanced CN/NFATc3 activation through synergistic action of both channels. In conclusion, TRPV4 channels contribute to pathological remodeling by promoting fibrosis and inducing TRPC6 upregulation through the activation of Ca 2+ -dependent CN/NFATc3 signaling. These results pose TRPV4 as a primary mediator of the pathological response.

Published
2024
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43. Therapeutic S100A8/A9 blockade inhibits myocardial and systemic inflammation and mitigates sepsis-induced myocardial dysfunction.

Author

Jakobsson G, Papareddy P, Andersson H, Mulholland M, Bhongir R, Ljungcrantz I, Engelbertsen D, Björkbacka H, Nilsson J, Manea A, Herwald H, Ruiz-Meana M, Rodríguez-Sinovas A, Chew M, and Schiopu A

Subjects
Animals, Humans, Mice, Endotoxemia complications, Endotoxemia drug therapy, Inflammation drug therapy, Lipopolysaccharides, Myocardium pathology, Calgranulin A antagonists & inhibitors, Calgranulin B metabolism, Heart Diseases drug therapy, Ventricular Dysfunction, Left drug therapy
Abstract

Background and Aims: The triggering factors of sepsis-induced myocardial dysfunction (SIMD) are poorly understood and are not addressed by current treatments. S100A8/A9 is a pro-inflammatory alarmin abundantly secreted by activated neutrophils during infection and inflammation. We investigated the efficacy of S100A8/A9 blockade as a potential new treatment in SIMD., Methods: The relationship between plasma S100A8/A9 and cardiac dysfunction was assessed in a cohort of 62 patients with severe sepsis admitted to the intensive care unit of Linköping University Hospital, Sweden. We used S100A8/A9 blockade with the small-molecule inhibitor ABR-238901 and S100A9 -/- mice for therapeutic and mechanistic studies on endotoxemia-induced cardiac dysfunction in mice., Results: In sepsis patients, elevated plasma S100A8/A9 was associated with left-ventricular (LV) systolic dysfunction and increased SOFA score. In wild-type mice, 5 mg/kg of bacterial lipopolysaccharide (LPS) induced rapid plasma S100A8/A9 increase and acute LV dysfunction. Two ABR-238901 doses (30 mg/kg) administered intraperitoneally with a 6 h interval, starting directly after LPS or at a later time-point when LV dysfunction is fully established, efficiently prevented and reversed the phenotype, respectively. In contrast, dexamethasone did not improve cardiac function compared to PBS-treated endotoxemic controls. S100A8/A9 inhibition potently reduced systemic levels of inflammatory mediators, prevented upregulation of inflammatory genes and restored mitochondrial function in the myocardium. The S100A9 -/- mice were protected against LPS-induced LV dysfunction to an extent comparable with pharmacologic S100A8/A9 blockade. The ABR-238901 treatment did not induce an additional improvement of LV function in the S100A9 -/- mice, confirming target specificity., Conclusion: Elevated S100A8/A9 is associated with the development of LV dysfunction in severe sepsis patients and in a mouse model of endotoxemia. Pharmacological blockade of S100A8/A9 with ABR-238901 has potent anti-inflammatory effects, mitigates myocardial dysfunction and might represent a novel therapeutic strategy for patients with severe sepsis., (© 2023. BioMed Central Ltd., part of Springer Nature.)

Published
2023
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45. Spontaneous reperfusion enhances succinate concentration in peripheral blood from stemi patients but its levels does not correlate with myocardial infarct size or area at risk.

Author

Consegal M, Barba I, García Del Blanco B, Otaegui I, Rodríguez-Palomares JF, Martí G, Serra B, Bellera N, Ojeda-Ramos M, Valente F, Carmona MÁ, Miró-Casas E, Sambola A, Lidón RM, Bañeras J, Barrabés JA, Rodríguez C, Benito B, Ruiz-Meana M, Inserte J, Ferreira-González I, and Rodríguez-Sinovas A

Subjects
Animals, Magnetic Resonance Imaging, Reperfusion, Succinic Acid, Swine, Treatment Outcome, Heart Failure, Myocardial Infarction pathology, Percutaneous Coronary Intervention, ST Elevation Myocardial Infarction
Abstract

Succinate is enhanced during initial reperfusion in blood from the coronary sinus in ST-segment elevation myocardial infarction (STEMI) patients and in pigs submitted to transient coronary occlusion. Succinate levels might have a prognostic value, as they may correlate with edema volume or myocardial infarct size. However, blood from the coronary sinus is not routinely obtained in the CathLab. As succinate might be also increased in peripheral blood, we aimed to investigate whether peripheral plasma concentrations of succinate and other metabolites obtained during coronary revascularization correlate with edema volume or infarct size in STEMI patients. Plasma samples were obtained from peripheral blood within the first 10 min of revascularization in 102 STEMI patients included in the COMBAT-MI trial (initial TIMI 1) and from 9 additional patients with restituted coronary blood flow (TIMI 2). Metabolite concentrations were analyzed by 1 H-NMR. Succinate concentration averaged 0.069 ± 0.0073 mmol/L in patients with TIMI flow ≤ 1 and was significantly increased in those with TIMI 2 at admission (0.141 ± 0.058 mmol/L, p < 0.05). However, regression analysis did not detect any significant correlation between most metabolite concentrations and infarct size, extent of edema or other cardiac magnetic resonance (CMR) variables. In conclusion, spontaneous reperfusion in TIMI 2 patients associates with enhanced succinate levels in peripheral blood, suggesting that succinate release increases overtime following reperfusion. However, early plasma levels of succinate and other metabolites obtained from peripheral blood does not correlate with the degree of irreversible injury or area at risk in STEMI patients, and cannot be considered as predictors of CMR variables.Trial registration: Registered at www.clinicaltrials.gov (NCT02404376) on 31/03/2015. EudraCT number: 2015-001000-58., (© 2023. The Author(s).)

Published
2023
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46. Interaction of Cardiovascular Nonmodifiable Risk Factors, Comorbidities and Comedications With Ischemia/Reperfusion Injury and Cardioprotection by Pharmacological Treatments and Ischemic Conditioning.

Author

Ferdinandy P, Andreadou I, Baxter GF, Bøtker HE, Davidson SM, Dobrev D, Gersh BJ, Heusch G, Lecour S, Ruiz-Meana M, Zuurbier CJ, Hausenloy DJ, and Schulz R

Subjects
Animals, Humans, Risk Factors, Heart Disease Risk Factors, Ischemia, Myocardial Reperfusion Injury drug therapy, Myocardial Reperfusion Injury prevention & control, Myocardial Reperfusion Injury metabolism, Ischemic Preconditioning, Myocardial, Ischemic Postconditioning, Myocardial Ischemia drug therapy, Myocardial Ischemia prevention & control
Abstract

Preconditioning, postconditioning, and remote conditioning of the myocardium enhance the ability of the heart to withstand a prolonged ischemia/reperfusion insult and the potential to provide novel therapeutic paradigms for cardioprotection. While many signaling pathways leading to endogenous cardioprotection have been elucidated in experimental studies over the past 30 years, no cardioprotective drug is on the market yet for that indication. One likely major reason for this failure to translate cardioprotection into patient benefit is the lack of rigorous and systematic preclinical evaluation of promising cardioprotective therapies prior to their clinical evaluation, since ischemic heart disease in humans is a complex disorder caused by or associated with cardiovascular risk factors and comorbidities. These risk factors and comorbidities induce fundamental alterations in cellular signaling cascades that affect the development of ischemia/reperfusion injury and responses to cardioprotective interventions. Moreover, some of the medications used to treat these comorbidities may impact on cardioprotection by again modifying cellular signaling pathways. The aim of this article is to review the recent evidence that cardiovascular risk factors as well as comorbidities and their medications may modify the response to cardioprotective interventions. We emphasize the critical need for taking into account the presence of cardiovascular risk factors as well as comorbidities and their concomitant medications when designing preclinical studies for the identification and validation of cardioprotective drug targets and clinical studies. This will hopefully maximize the success rate of developing rational approaches to effective cardioprotective therapies for the majority of patients with multiple comorbidities. SIGNIFICANCE STATEMENT: Ischemic heart disease is a major cause of mortality; however, there are still no cardioprotective drugs on the market. Most studies on cardioprotection have been undertaken in animal models of ischemia/reperfusion in the absence of comorbidities; however, ischemic heart disease develops with other systemic disorders (e.g., hypertension, hyperlipidemia, diabetes, atherosclerosis). Here we focus on the preclinical and clinical evidence showing how these comorbidities and their routine medications affect ischemia/reperfusion injury and interfere with cardioprotective strategies., (Copyright © 2023 by The Author(s).)

Published
2023
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47. Connexin 43 in Mitochondria: What Do We Really Know About Its Function?

Author

Boengler K, Leybaert L, Ruiz-Meana M, and Schulz R

Abstract

Connexins are known for their ability to mediate cell-cell communication via gap junctions and also form hemichannels that pass ions and molecules over the plasma membrane when open. Connexins have also been detected within mitochondria, with mitochondrial connexin 43 (Cx43) being the best studied to date. In this review, we discuss evidence for Cx43 presence in mitochondria of cell lines, primary cells and organs and summarize data on its localization, import and phosphorylation status. We further highlight the influence of Cx43 on mitochondrial function in terms of respiration, opening of the mitochondrial permeability transition pore and formation of reactive oxygen species, and also address the presence of a truncated form of Cx43 termed Gja1-20k. Finally, the role of mitochondrial Cx43 in pathological conditions, particularly in the heart, is discussed., 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 Boengler, Leybaert, Ruiz-Meana and Schulz.)

Published
2022
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48. Cardiac fibroblasts display endurance to ischemia, high ROS control and elevated respiration regulated by the JAK2/STAT pathway.

Author

Beà A, Valero JG, Irazoki A, Lana C, López-Lluch G, Portero-Otín M, Pérez-Galán P, Inserte J, Ruiz-Meana M, Zorzano A, Llovera M, and Sanchis D

Subjects
Animals, Fibroblasts metabolism, Ischemia, Proto-Oncogene Proteins c-bcl-2 metabolism, Rats, Reactive Oxygen Species metabolism, Respiration, STAT3 Transcription Factor genetics, STAT3 Transcription Factor metabolism, Signal Transduction, Antioxidants, Janus Kinase 2 genetics, Janus Kinase 2 metabolism
Abstract

Cardiovascular diseases are the leading cause of death globally and more than four out of five cases are due to ischemic events. Cardiac fibroblasts (CF) contribute to normal heart development and function, and produce the post-ischemic scar. Here, we characterize the biochemical and functional aspects related to CF endurance to ischemia-like conditions. Expression data mining showed that cultured human CF (HCF) express more BCL2 than pulmonary and dermal fibroblasts. In addition, gene set enrichment analysis showed overrepresentation of genes involved in the response to hypoxia and oxidative stress, respiration and Janus kinase (JAK)/Signal transducer and Activator of Transcription (STAT) signaling pathways in HCF. BCL2 sustained survival and proliferation of cultured rat CF, which also had higher respiration capacity and reactive oxygen species (ROS) production than pulmonary and dermal fibroblasts. This was associated with higher expression of the electron transport chain (ETC) and antioxidant enzymes. CF had high phosphorylation of JAK2 and its effectors STAT3 and STAT5, and their inhibition reduced viability and respiration, impaired ROS control and reduced the expression of BCL2, ETC complexes and antioxidant enzymes. Together, our results identify molecular and biochemical mechanisms conferring survival advantage to experimental ischemia in CF and show their control by the JAK2/STAT signaling pathway. The presented data point to potential targets for the regulation of cardiac fibrosis and also open the possibility of a general mechanism by which somatic cells required to acutely respond to ischemia are constitutively adapted to survive it., (© 2021 The Authors. The FEBS Journal published by John Wiley & Sons Ltd on behalf of Federation of European Biochemical Societies.)

Published
2022
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49. Calpains as Potential Therapeutic Targets for Myocardial Hypertrophy.

Author

Aluja D, Delgado-Tomás S, Ruiz-Meana M, Barrabés JA, and Inserte J

Subjects
Animals, Calcium-Binding Proteins, Cardiomegaly drug therapy, Calpain metabolism, Heart Failure drug therapy
Abstract

Despite advances in its treatment, heart failure remains a major cause of morbidity and mortality, evidencing an urgent need for novel mechanism-based targets and strategies. Myocardial hypertrophy, caused by a wide variety of chronic stress stimuli, represents an independent risk factor for the development of heart failure, and its prevention constitutes a clinical objective. Recent studies performed in preclinical animal models support the contribution of the Ca 2+ -dependent cysteine proteases calpains in regulating the hypertrophic process and highlight the feasibility of their long-term inhibition as a pharmacological strategy. In this review, we discuss the existing evidence implicating calpains in the development of cardiac hypertrophy, as well as the latest advances in unraveling the underlying mechanisms. Finally, we provide an updated overview of calpain inhibitors that have been explored in preclinical models of cardiac hypertrophy and the progress made in developing new compounds that may serve for testing the efficacy of calpain inhibition in the treatment of pathological cardiac hypertrophy.

Published
2022
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50. Defective dimerization of FoF1-ATP synthase secondary to glycation favors mitochondrial energy deficiency in cardiomyocytes during aging.

Author

Bou-Teen D, Fernandez-Sanz C, Miro-Casas E, Nichtova Z, Bonzon-Kulichenko E, Casós K, Inserte J, Rodriguez-Sinovas A, Benito B, Sheu SS, Vázquez J, Ferreira-González I, and Ruiz-Meana M

Subjects
Adenosine Triphosphate metabolism, Animals, Calcium metabolism, Dimerization, Glycation End Products, Advanced chemistry, Glycation End Products, Advanced metabolism, Mice, Mitochondrial Permeability Transition Pore, Aging metabolism, Aging physiology, Mitochondria, Heart metabolism, Mitochondrial Proton-Translocating ATPases chemistry, Mitochondrial Proton-Translocating ATPases metabolism, Myocytes, Cardiac metabolism
Abstract

Aged cardiomyocytes develop a mismatch between energy demand and supply, the severity of which determines the onset of heart failure, and become prone to undergo cell death. The FoF1-ATP synthase is the molecular machine that provides >90% of the ATP consumed by healthy cardiomyocytes and is proposed to form the mitochondrial permeability transition pore (mPTP), an energy-dissipating channel involved in cell death. We investigated whether aging alters FoF1-ATP synthase self-assembly, a fundamental biological process involved in mitochondrial cristae morphology and energy efficiency, and the functional consequences this may have. Purified heart mitochondria and cardiomyocytes from aging mice displayed an impaired dimerization of FoF1-ATP synthase (blue native and proximity ligation assay), associated with abnormal mitochondrial cristae tip curvature (TEM). Defective dimerization did not modify the in vitro hydrolase activity of FoF1-ATP synthase but reduced the efficiency of oxidative phosphorylation in intact mitochondria (in which membrane architecture plays a fundamental role) and increased cardiomyocytes' susceptibility to undergo energy collapse by mPTP. High throughput proteomics and fluorescence immunolabeling identified glycation of 5 subunits of FoF1-ATP synthase as the causative mechanism of the altered dimerization. In vitro induction of FoF1-ATP synthase glycation in H9c2 myoblasts recapitulated the age-related defective FoF1-ATP synthase assembly, reduced the relative contribution of oxidative phosphorylation to cell energy metabolism, and increased mPTP susceptibility. These results identify altered dimerization of FoF1-ATP synthase secondary to enzyme glycation as a novel pathophysiological mechanism involved in mitochondrial cristae remodeling, energy deficiency, and increased vulnerability of cardiomyocytes to undergo mitochondrial failure during aging., (© 2022 The Authors. Aging Cell published by Anatomical Society and John Wiley & Sons Ltd.)

Published
2022
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