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Extra cellular matrix remodelling after heterotopic rat heart transplantation: gene expression profiling and involvement of ED-A+ fibronectin, alpha-smooth muscle actin and B+ tenascin-C in chronic cardiac allograft rejection

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Abstract

Chronic cardiac rejection is represented by cardiac allograft vasculopathy (CAV) and cardiac interstitial fibrosis (CIF) known to cause severe complications. These processes are accompanied by remarkable changes in the cardiac extra cellular matrix (cECM). The aim of our study was to analyse the cECM remodelling in chronic rejection and to elucidate a potential role of ED-A domain containing fibronectin (ED-A+ Fn), alpha smooth muscle actin (ASMA) and B domain containing tenascin-C (B+ Tn-C). A model of chronic rejection after heterotopic rat heart transplantation was used. Allografts, recipient and control hearts were subjected to histological assessment of rejection grade, to real-time PCR based analysis of 84 genes of ECM and adhesion molecules and to immunofluorescence labelling procedures, including ED-A+ Fn, ASMA and B+ Tn-C antibodies. Histological analysis revealed different grades of chronic rejection. By gene expression analysis, a relevant up-regulation of the majority of ECM genes in association with chronic rejection could be shown. For 8 genes, there was a relevant up-regulation in allografts as well as in the corresponding recipient hearts. Association of ASMA positive cells with the grade of chronic rejection could be proven. In CAV and also in CIF there were extensive co-depositions of ED-A+ Fn, ASMA and B+ Tn-C. In conclusion, chronic cardiac allograft rejection is associated with a cECM remodelling. ASMA protein deposition in CAV, and CIF is a valuable marker to detect chronic rejection. Interactions of VSMCs and Fibro-/Myofibroblasts with ED-A+ Fn and B+ Tn-C might functionally contribute to the development of chronic cardiac rejection.

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Acknowledgments

The authors would like to thank Katrin Hornung and Claudia Seliger for excellent technical assistance. The research leading to the results has received funding from the European Community’s Seventh Framework Programme (FP7/2007-2013) under grant agreement no. Health-F2-2008-201342 (ADAMANT).

Conflict of interest

Dario Neri is a co-founder and shareholder of Philogen, the company which owns the rights over the F8 antibody.

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Authors and Affiliations

  1. Department of Internal Medicine I, University Hospital of Jena, Erlanger Allee 101, 07740, Jena, Germany

    Marcus Franz, B. R. Brehm, M. Fritzenwanger & H. R. Figulla

  2. Department of Cardiothoracic Surgery, University Hospital of Jena, Jena, Germany

    K. Grün & K. Hekmat

  3. Institute of Pathology, University Hospital Jena, Jena, Germany

    P. Richter & A. Berndt

  4. Institute of Pharmaceutical Sciences, Swiss Federal Institute of Technology (ETH), Zurich, Switzerland

    D. Neri

  5. Institute of Pathology, HELIOS-Klinikum Erfurt, Erfurt, Germany

    H. Kosmehl

  6. Clinic for Thoracic and Cardiovascular Surgery, Heart Center North Rhine-Westphalia, Ruhr-University of Bochum, Bad Oeynhausen, Germany

    J. Gummert & A. Renner

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  1. Marcus Franz
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Correspondence to Marcus Franz.

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M. Franz and K. Grün contributed equally to the study.

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Franz, M., Grün, K., Richter, P. et al. Extra cellular matrix remodelling after heterotopic rat heart transplantation: gene expression profiling and involvement of ED-A+ fibronectin, alpha-smooth muscle actin and B+ tenascin-C in chronic cardiac allograft rejection. Histochem Cell Biol 134, 503–517 (2010). https://doi.org/10.1007/s00418-010-0750-6

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