miR-146a attenuates apoptosis and modulates autophagy by targeting TAF9b/P53 pathway in doxorubicin-induced cardiotoxicity

  • Cell Death Dis. 2019 Sep 11;10(9):668. doi: 10.1038/s41419-019-1901-x.
Jian-An Pan  1 ,  Yong Tang  2 ,  Jian-Ying Yu  1 ,  Hui Zhang  1 ,  Jun-Feng Zhang  1 ,  Chang-Qian Wang  1 ,  Jun Gu  3
Affiliations
  • 1. Department of Cardiology, Shanghai Ninth People's Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, People's Republic of China.
  • 2. Department of Hematology, Shanghai Ninth People's Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, People's Republic of China.
  • 3. Department of Cardiology, Shanghai Ninth People's Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, People's Republic of China. [email protected].
PMID: 31511497 DOI: 10.1038/s41419-019-1901-x
Abstract

Clinical therapy of doxorubicin (DOX) is limited due to its cardiotoxicity. miR-146a was proved as a protective factor in many cardiovascular diseases, but its role in chronic DOX-induced cardiotoxicity is unclear. The objective of this study was to demonstrate the role of miR-146a in low-dose long-term DOX-induced cardiotoxicity. Experiments have shown that DOX intervention caused a dose-dependent and time-dependent cardiotoxicity involving the increased of Apoptosis and dysregulation of Autophagy. The cardiotoxicity was inhibited by overexpressed miR-146a and was more severe when miR-146a was downgraded. Further research proved that miR-146a targeted TATA-binding protein (TBP) associated factor 9b (TAF9b), a coactivator and stabilizer of P53, indirectly destroyed the stability of P53, thereby inhibiting Apoptosis and improving Autophagy in cardiomyocytes. Besides, miR-146a knockout mice were used for in vivo validation. In the DOX-induced model, miR-146a deficiency made it worse whether in cardiac function, cardiomyocyte Apoptosis or basal level of Autophagy, than wild-type. In conclusion, miR-146a partially reversed the DOX-induced cardiotoxicity by targeting TAF9b/P53 pathway to attenuate Apoptosis and adjust Autophagy levels.

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