title: miR-21 promotes fibrosis in an acute cardiac allograft transplantation model.
abstract: OBJECTIVE
  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.
  
  
  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.
  
  
  CONCLUSIONS
  Thus, inhibition of miR-21 is a novel strategy to target fibrosis development in cardiac allografts.
authors: Institute of Molecular and Translational Therapeutic Strategies (IMTTS), OE 8886, Hannover Medical School, Carl-Neuberg Strasse 1, 30625 Hannover, Germany.
authors: Shashi Kumar
authors: SK
authors: Gupta
authors: TSI Laboratory, University Heart Center, Hamburg, Germany.
authors: Ryo
authors: R
authors: Itagaki
authors: Institute of Immunology, Hannover Medical School, Hannover, Germany.
authors: Xiang
authors: X
authors: Zheng
authors: Institute of Molecular and Translational Therapeutic Strategies (IMTTS), OE 8886, Hannover Medical School, Carl-Neuberg Strasse 1, 30625 Hannover, Germany.
authors: Sandor
authors: S
authors: Batkai
authors: Institute of Molecular and Translational Therapeutic Strategies (IMTTS), OE 8886, Hannover Medical School, Carl-Neuberg Strasse 1, 30625 Hannover, Germany.
authors: Sabrina
authors: S
authors: Thum
authors: Clinic for Immunology and Rheumatology, Hannover Medical School, Hannover, Germany.
authors: Fareed
authors: F
authors: Ahmad
authors: Department of Cardiovascular Sciences, University of Leuven, Leuven, Belgium.
authors: Lucas N
authors: LN
authors: Van Aelst
authors: Department of Hematology, Hemostasis, Oncology and Stem Cell Transplantation, Hannover Medical School, Hannover, Germany.
authors: Amit
authors: A
authors: Sharma
authors: Institute of Molecular and Translational Therapeutic Strategies (IMTTS), OE 8886, Hannover Medical School, Carl-Neuberg Strasse 1, 30625 Hannover, Germany.
authors: Maria-Teresa
authors: MT
authors: Piccoli
authors: Experimental Pharmacology and Toxicology, Hamburg, Germany.
authors: Florian
authors: F
authors: Weinberger
authors: Institute of Molecular and Translational Therapeutic Strategies (IMTTS), OE 8886, Hannover Medical School, Carl-Neuberg Strasse 1, 30625 Hannover, Germany.
authors: Jan
authors: J
authors: Fiedler
authors: Department of Hematology, Hemostasis, Oncology and Stem Cell Transplantation, Hannover Medical School, Hannover, Germany.
authors: Michael
authors: M
authors: Heuser
authors: Department of Cardiovascular Sciences, University of Leuven, Leuven, Belgium Department of Cardiology, Faculty of Health Medicine and Life Sciences, Maastricht University, Maastricht, Netherlands.
authors: Stephane
authors: S
authors: Heymans
authors: Transplant Immunology, Integrated Research and Treatment Centre Transplantation, Hannover Medical School, Hannover, Germany German Center for Infection Research (DZIF), Braunschweig, Germany.
authors: Christine S
authors: CS
authors: Falk
authors: Institute of Immunology, Hannover Medical School, Hannover, Germany.
authors: Reinhold
authors: R
authors: Förster
authors: TSI Laboratory, University Heart Center, Hamburg, Germany.
authors: Sonja
authors: S
authors: Schrepfer
authors: 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.
authors: Thomas
authors: T
authors: Thum
mesh_terms: D064591:Allografts / Q000187:drug effects / Q000378:metabolism; D000818:Animals; D018925:Chemokines / Q000235:genetics; D004195:Disease Models, Animal; D005355:Fibrosis / Q000235:genetics; D006085:Graft Survival / Q000235:genetics*; D006331:Heart Diseases / Q000235:genetics* / Q000473:pathology*; D016027:Heart Transplantation / Q000379:methods; D015850:Interleukin-6 / Q000494:pharmacology; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D035683:MicroRNAs / Q000235:genetics*; D009206:Myocardium / Q000378:metabolism; D014184:Transplantation, Homologous / Q000379:methods
chemical_list: D018925:Chemokines; D015850:Interleukin-6; C531950:MIRN21 microRNA, mouse; D035683:MicroRNAs
keywords: Allograft; Cardiac transplantation; Fibrocyte; Fibrosis; MiRNA-21