Shashi Kumar Gupta1, Ryo Itagaki2, Xiang Zheng3, Sandor Batkai1, Sabrina Thum1, Fareed Ahmad4, Lucas N Van Aelst5, Amit Sharma6, Maria-Teresa Piccoli1, Florian Weinberger7, Jan Fiedler1, Michael Heuser6, Stephane Heymans8, Christine S Falk9, Reinhold Förster3, Sonja Schrepfer2, Thomas Thum10. 1. Institute of Molecular and Translational Therapeutic Strategies (IMTTS), OE 8886, Hannover Medical School, Carl-Neuberg Strasse 1, 30625 Hannover, Germany. 2. TSI Laboratory, University Heart Center, Hamburg, Germany. 3. Institute of Immunology, Hannover Medical School, Hannover, Germany. 4. Clinic for Immunology and Rheumatology, Hannover Medical School, Hannover, Germany. 5. Department of Cardiovascular Sciences, University of Leuven, Leuven, Belgium. 6. Department of Hematology, Hemostasis, Oncology and Stem Cell Transplantation, Hannover Medical School, Hannover, Germany. 7. Experimental Pharmacology and Toxicology, Hamburg, Germany. 8. Department of Cardiovascular Sciences, University of Leuven, Leuven, Belgium Department of Cardiology, Faculty of Health Medicine and Life Sciences, Maastricht University, Maastricht, Netherlands. 9. Transplant Immunology, Integrated Research and Treatment Centre Transplantation, Hannover Medical School, Hannover, Germany German Center for Infection Research (DZIF), Braunschweig, Germany. 10. Institute of Molecular and Translational Therapeutic Strategies (IMTTS), OE 8886, Hannover Medical School, Carl-Neuberg Strasse 1, 30625 Hannover, Germany REBIRTH Excellence Cluster, Hannover Medical School, Hannover, Germany National Heart and Lung Institute, Imperial College London, London, UK thum.thomas@mh-hannover.de.
Abstract
AIMS: Cardiac transplantation is the only curative therapy for end-stage heart failure. Fibrosis is one of the major causes for impaired function of cardiac allografts. MicroRNAs, a class of small non-coding RNAs, play a critical role in the development of cardiovascular disease, but the role of microRNAs in cardiac allograft failure is not well understood. METHODS AND RESULTS: To uncover a role of microRNAs during cardiac graft fibrosis, we generated global microRNA profiles in allogeneic (BALB/c in C57BL/6N) and isogeneic (C57BL/6N in C57BL/6N) murine hearts after transplantation. miR-21 together with cardiac fibrosis was increased in cardiac allografts compared with isografts. Likewise, patients with cardiac rejection after heart transplantation showed increased cardiac miR-21 levels. miR-21 was induced upon treatment with IL-6 in a monocyte cell line. Overexpression of miR-21 in this monocyte cell line activated a fibrotic gene programme and promoted monocyte-to-fibrocyte transition together with activation of chemokine (C-C) motif ligand 2 (monocyte chemoattractant protein 1) via the phosphatase and tensin homologue/activator protein 1 regulatory axis. In vivo, both genetic and pharmacological inhibition of miR-21 successfully reduced fibrosis and fibrocyte accumulation in cardiac allografts. CONCLUSION: Thus, inhibition of miR-21 is a novel strategy to target fibrosis development in cardiac allografts. Published on behalf of the European Society of Cardiology. All rights reserved.
AIMS: Cardiac transplantation is the only curative therapy for end-stage heart failure. Fibrosis is one of the major causes for impaired function of cardiac allografts. MicroRNAs, a class of small non-coding RNAs, play a critical role in the development of cardiovascular disease, but the role of microRNAs in cardiac allograft failure is not well understood. METHODS AND RESULTS: To uncover a role of microRNAs during cardiac graft fibrosis, we generated global microRNA profiles in allogeneic (BALB/c in C57BL/6N) and isogeneic (C57BL/6N in C57BL/6N) murine hearts after transplantation. miR-21 together with cardiac fibrosis was increased in cardiac allografts compared with isografts. Likewise, patients with cardiac rejection after heart transplantation showed increased cardiac miR-21 levels. miR-21 was induced upon treatment with IL-6 in a monocyte cell line. Overexpression of miR-21 in this monocyte cell line activated a fibrotic gene programme and promoted monocyte-to-fibrocyte transition together with activation of chemokine (C-C) motif ligand 2 (monocyte chemoattractant protein 1) via the phosphatase and tensin homologue/activator protein 1 regulatory axis. In vivo, both genetic and pharmacological inhibition of miR-21 successfully reduced fibrosis and fibrocyte accumulation in cardiac allografts. CONCLUSION: Thus, inhibition of miR-21 is a novel strategy to target fibrosis development in cardiac allografts. Published on behalf of the European Society of Cardiology. All rights reserved.
Authors: Carmen C Sucharov; David P Kao; J David Port; Anis Karimpour-Fard; Robert A Quaife; Wayne Minobe; Karin Nunley; Brian D Lowes; Edward M Gilbert; Michael R Bristow Journal: JCI Insight Date: 2017-01-26
Authors: Maryam Syed; Jana P Ball; Keisa W Mathis; Michael E Hall; Michael J Ryan; Marc E Rothenberg; Licy L Yanes Cardozo; Damian G Romero Journal: Am J Physiol Endocrinol Metab Date: 2018-08-28 Impact factor: 4.310