Journal
MOLECULAR THERAPY
Volume 27, Issue 1, Pages 17-28Publisher
CELL PRESS
DOI: 10.1016/j.ymthe.2018.11.004
Keywords
-
Categories
Funding
- Deutsche Forschungsgemeinschaft (DFG) [GU 1664-1-1]
- REBIRTH Excellence Cluster
- Fondation Leducq (MIRVAD [MicroRNA-Based Therapeutic Strategies in Vascular Disease])
- European Union
- BMBF grant e:Bio-Modul II-Verbundprojekt: CaRNAtion [031L0075C]
Ask authors/readers for more resources
Improved therapy of cancer has significantly increased the lifespan of patients. However, cancer survivors face an increased risk of cardiovascular complications due to adverse effects of cancer therapies. The chemotherapy drug doxorubicin is well known to induce myofibril damage and cardiac atrophy. Our aim was to test potential counteracting effects of the prohypertrophic miR-212/132 family in doxorubicin-induced cardiotoxicity. In vitro, overexpression of the pro-hypertrophic miR-212/132 cluster in primary rodent and human iPSC-derived cardiomyocytes inhibited doxorubicin-induced toxicity. Next, a disease model of doxorubicin-induced cardiotoxicity was established in male C57BL/6N mice. Mice were administered either adeno-associated virus (AAV) 9-control or AAV9miR- 212/132 to achieve myocardial overexpression of the miR-212/132 cluster. AAV9-mediated overexpression limited cardiac atrophy by increasing left ventricular mass and wall thickness, decreased doxorubicin-mediated apoptosis, and prevented myofibril damage. Based on a transcriptomic profiling we identified fat storage-inducing transmembrane protein 2 (Fitm2) as a novel target and downstream effector molecule responsible, at least in part, for the observed miR212/ 132 anti-cardiotoxic effects. Overexpression of Fitm2 partially reversed the effects of miR-212/132. Overexpression of the miR-212/132 family reduces development of doxorubicin- induced cardiotoxicity and thus could be a therapeutic entry point to limit doxorubicin-mediated adverse cardiac effects.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available