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

• Published in: Cell death & disease Vol. 10; no. 9; pp. 668 - 15
• Main Authors: Pan, Jian-An, Tang, Yong, Yu, Jian-Ying, Zhang, Hui, Zhang, Jun-Feng, Wang, Chang-Qian, Gu, Jun
• Format: Journal Article
• Language: English
• Published: England Springer Nature B.V 11.09.2019; Nature Publishing Group UK
• Subjects: 3' Untranslated Regions; Animals; Apoptosis; Apoptosis - drug effects; Apoptosis - genetics; Autophagy; Autophagy - drug effects; Autophagy - genetics; Cardiomyocytes; Cardiotoxicity; Cardiotoxicity - genetics; Cardiotoxicity - metabolism; Cardiovascular diseases; Cell Line; Cell Survival - drug effects; Cell Survival - genetics; Doxorubicin; Doxorubicin - toxicity; Heart Injuries - chemically induced; Heart Injuries - genetics; Heart Injuries - metabolism; Humans; Male; Mice; Mice, Knockout; MicroRNAs - genetics; MicroRNAs - metabolism; Microscopy, Electron, Transmission; Myocytes, Cardiac - drug effects; Myocytes, Cardiac - metabolism; Myocytes, Cardiac - pathology; Myocytes, Cardiac - ultrastructure; p53 Protein; Phagocytosis; TATA-binding protein; TATA-Binding Protein Associated Factors - genetics; TATA-Binding Protein Associated Factors - metabolism; Transcription Factor TFIID - genetics; Transcription Factor TFIID - metabolism; Tumor Suppressor Protein p53 - genetics; Tumor Suppressor Protein p53 - metabolism
• ISSN: 2041-4889; 2041-4889
• DOI: 10.1038/s41419-019-1901-x

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.