miR-21 promotes fibrosis in an acute cardiac allograft transplantation model

Shashi Kumar Gupta, Ryo Itagaki, Xiang Zheng, Sandor Batkai, Sabrina Thum, Fareed Ahmad, Lucas N. Van Aelst, Amit Sharma, Maria-Teresa Piccoli, Florian Weinberger, Jan Fiedler, Michael Heuser, Stephane Heymans, Christine S. Falk, Reinhold Foerster, Sonja Schrepfer, Thomas Thum*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

55 Citations (Web of Science)

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.
Original languageEnglish
Pages (from-to)215-226
JournalCardiovascular Research
Volume110
Issue number2
DOIs
Publication statusPublished - 15 May 2016

Keywords

  • MiRNA-21
  • Fibrosis
  • Cardiac transplantation
  • Fibrocyte
  • Allograft

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