Journal
CARDIOVASCULAR RESEARCH
Volume 110, Issue 2, Pages 215-226Publisher
OXFORD UNIV PRESS
DOI: 10.1093/cvr/cvw030
Keywords
MiRNA-21; Fibrosis; Cardiac transplantation; Fibrocyte; Allograft
Categories
Funding
- IFB-Tx BMBF [01EO1302]
- German Research Foundation (DFG) [SCHR332/4-1]
- [SFB738]
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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.
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