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---Procedencia:
Institución:Institut de Recerca Hospital Vall d'Hebron
Contacto correo-e:arodriguez@ir.vhebron.net
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Mitochondria and connexin 43 in myocardial reperfusion injury and cardioprotection
Supervisors: David Garcia-Dorado, and Antonio Rodriguez-Sinovas, BCN
Co-Supervisor: Thomas Noll, GI
Aims: The present project aims to elucidate molecular mechanisms of cardioprotection with the final goal of identifying new therapeutic targets allowing the development of interventions able to limit cardiomyocyte death in patients with myocardial infarction receiving reperfusion therapy. In particular, we will characterize the role of connexin 43 (Cx43), in the genesis of endogenous cardioprotection, with focus on its mitochondrial localization.
Current state of relevant research and own preliminary work: Cx43 has important functions unrelated to gap junction-mediated intercellular communication (1), and plays an important role in ischemic preconditioning protection, demonstrated by the failure to protect Cx43 deficient animals (Cx43+/-). However, the lack of effects of preconditioning on electrical coupling, and the observation that Cx43 was also essential to precondition isolated cardiomyocytes (2) indicated that the role of Cx43 in preconditioning protection should be independent from changes in gap junction-mediated communication. Because mitochondria are important elements in preconditioning, we hypothesized that Cx43 could participate in the preconditioning cascade by modulating mitochondrial function, and provided antibody-based evidence of the presence of Cx43 in the inner mitochondrial membrane of cardiomyocytes including flow cytometry, confocal co-localization, and immunoelectron microscopy with gold bea!
d-labelled antibodies in highly purified mitochondrial preparations from mice, rat, pig and human hearts (3), as well as antibody-independent methods (4). The results unambiguously demonstrated the presence of Cx43 in the inner membrane, that it arrives there by using the general TOM (translocase of the outer membrane)/TIM (translocase of the inner membrane) import system (5), and that this occurs in subsarcolemmal but not interfibrillar mitochondria (6). We have demonstrated by an array of methods that mitochondrial Cx43 modulates K+ influx to mitochondria (7), which has been corroborated by other groups. By using a mice model in which Cx43 has been completely replaced by Cx32, with different biochemical properties, we have proven that Cx43 is an important modulator of mitochondrial respiration and energetic metabolism (8).
Work Programme: Based on previous work from our group we propose a research programme aimed to elucidate the role of Cx43 in myocardial pathophysiology with focus on ischemia-reperfusion by gap-junction dependent and independent mechanisms, these latter including cell membrane hemichannels, and, in particular, mitochondria.
To achieve this goal we proposed the coordinated development of experiments in an array of preparations from mitochondria, to isolated or in situ hearts and human right atrial tissue samples. Main research task will include analysis of cell signalling, mitochondrial function, metabolism, and electrical and mechanical function in the presence of genetic and pharmacological interventions, and in their absence, and the response to ischemia-reperfusion in each condition.
Gap junction-mediated effects on ischemia-reperfusion injury and in endogenous protection by different manouvers (ischemic and pharmacological pre- and postconditioning and remote conditioning) will be assessed in in situ and isolated hearts by using peptide-derived specific openers and non-specific uncouplers in genetic models of Cx43 deficiency. Gap junction independent effects of Cx43 will be studied using hemichannel antagonists (Gap27) and blockers of different mitochondrial ionic channels in these models of Cx43 deficiency. Ischemia-reperfusion injury will be analyzed by determining infarct size, arrhythmogenesis, and functional recovery in these models. Gap junction-independent effects will be confirmed in isolated cells by using the same gap junction or hemichannel uncouplers and openers. Mechanistics insights will be conducted mainly in isolated cells, and in mitochondrial preparations.
Cooperation among partners regarding other subprojects: Cooperations will be established with other partners by which students allocated to other subprojects carried-out in Giessen will develop part of their experimental tasks in Barcelona. Regarding the project of H. M. Piper, the influence of Cx43 on endothelial tolerance to ischemia-reperfusion will be studied in in-vivo experiments in Cx43 deficient animals, and in animals in which Cx43 has been replaced by Cx32.
Literature (* own):
1. Rodriguez-Sinovas A et al. Prog Biophys Mol Biol 2007; 94: 219-32
2. Heinzel FR et al. Circ Res 2005; 97: 583-6.
3. Boengler K et al . Cardiovasc Res 2005; 67: 234-44.
4. Ruiz-Meana M et al. Cardiovasc Res. 2008; 77: 325-333.
5. Rodriguez-Sinovas A et al. Circ Res 2006; 99: 93-101.
6. Boengler et al, Bas Res Cardiol 2009; 104: 141-147.
7. Miró-Casas et al. Cardiovasc Res 2009; 83: 747-756.
8. Rodriguez-Sinovas et al. J Physiol 2010; 588: 1139-1151.
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Información complementaria de la oferta:
Supervisors: David Garcia-Dorado, and Antonio Rodriguez-Sinovas, BCN
Co-Supervisor: Thomas Noll, GI
Lab Cardiologia Experimental
Hospital Universitari Vall d'Hebron,
Institut de Recerca (VHIR),
Universitat Autònoma de Barcelona,
Passeig Vall d'Hebron 119-129
08035 Barcelona, Spain
http://www.ir.vhebron.net
http://cardioexperimentalvh.onmedic.org
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