Theranostics 2017; 7(16):3842-3855. doi:10.7150/thno.19764

Research Paper

A Circular RNA Binds To and Activates AKT Phosphorylation and Nuclear Localization Reducing Apoptosis and Enhancing Cardiac Repair

Yan Zeng1,2, 3*, William W. Du1, 2*, Yingya Wu1, 2*, Zhenguo Yang1, 2*, Faryal Mehwish Awan1, 2, Xiangmin Li1, 2, 4, Weining Yang1, Chao Zhang1, 2, Qi Yang1, 2, Albert Yee1, 2, Yu Chen5, Fenghua Yang6, Huan Sun7, Ren Huang6, Albert J Yee1, Ren-Ke Li7, Zhongkai Wu5, Peter H Backx7, 8, Burton B Yang1, 2, 9✉

1. Sunnybrook Research Institute, Sunnybrook Health Sciences Centre, Toronto, Canada;
2. Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Canada;
3. Department of Cardiovascular Medicine, Second Xiangya Hospital of Central South University, 139 Middle Ren-Min Road, Changsha, Hunan, P.R. China 410011, China;
4. State Key Laboratory of Applied Microbiology Southern China, Guangdong Institute of Microbiology, Guangzhou, 510070, China;
5. The First Hospital, Sun Yat-Sen University, Guangzhou, China;
6. Guangdong Laboratory Animals Monitoring Institute, Guangzhou 510663, Guangdong, China;
7. Toronto General Research Institute, University Health Network, Toronto, Canada;
8. Department of Biology, York University, Toronto, Canada;
9. Institute of Medical Science, University of Toronto, Toronto, Canada.
* These authors contributed equally.

Abstract

As central nodes in cardiomyocyte signaling, nuclear AKT appears to play a cardio-protective role in cardiovascular disease. Here we describe a circular RNA, circ-Amotl1 that is highly expressed in neonatal human cardiac tissue, and potentiates AKT-enhanced cardiomyocyte survival. We hypothesize that circ-Amotl1 binds to PDK1 and AKT1, leading to AKT1 phosphorylation and nuclear translocation. In primary cardiomyocytes, epithelial cells, and endothelial cells, we found that forced circ-Amotl1 expression increased the nuclear fraction of pAKT. We further detected increased nuclear pAKT in circ-Amotl1-treated hearts. In vivo, circ-Amotl1 expression was also found to be protective against Doxorubicin (Dox)-induced cardiomyopathy. Putative PDK1- and AKT1-binding sites were then identified in silico. Blocking oligonucleotides could reverse the effects of exogenous circ-Amotl1. We conclude that circ-Amotl1 physically binds to both PDK1 and AKT1, facilitating the cardio-protective nuclear translocation of pAKT.

Keywords: circ-Amotl1, AKT, PDK, apoptosis, heart repair.

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How to cite this article:
Zeng Y, Du WW, Wu Y, Yang Z, Awan FM, Li X, Yang W, Zhang C, Yang Q, Yee A, Chen Y, Yang F, Sun H, Huang R, Yee AJ, Li RK, Wu Z, Backx PH, Yang BB. A Circular RNA Binds To and Activates AKT Phosphorylation and Nuclear Localization Reducing Apoptosis and Enhancing Cardiac Repair. Theranostics 2017; 7(16):3842-3855. doi:10.7150/thno.19764. Available from http://www.thno.org/v07p3842.htm