miR-301a-PTEN-AKT Signaling Induces Cardiomyocyte Proliferation and Promotes Cardiac Repair Post-MI

Lixiao Zhen; Qian Zhao; Jinhui Lü; Shengqiong Deng; Zhen Xu; Lin Zhang; Yuzhen Zhang; Huimin Fan; Xiongwen Chen; Zhongmin Liu; Yuying Gu; Zuoren Yu

doi:10.1016/j.omtn.2020.08.033

miR-301a-PTEN-AKT Signaling Induces Cardiomyocyte Proliferation and Promotes Cardiac Repair Post-MI

Mol Ther Nucleic Acids. 2020 Aug 29:22:251-262. doi: 10.1016/j.omtn.2020.08.033. eCollection 2020 Dec 4.

Authors

Affiliations

¹ Key Laboratory of Arrhythmias of the Ministry of Education of China, Research Center for Translational Medicine, Shanghai East Hospital, Tongji University School of Medicine, 150 Jimo Road, Shanghai 200120, China.
² Shanghai Gongli Hospital, The Second Military Medical University, Shanghai, China.
³ Cardiovascular Research Center, Temple University School of Medicine, Philadelphia, PA 19122, USA.

Abstract

Adult hearts are hard to recover after cardiac injury due to the limited proliferative ability of cardiomyocytes. Emerging evidence indicates the induction of cell cycle reentry of cardiomyocytes by special treatment or stimulation, which offers adult heart regenerative potential. Herein, a microRNA (miRNA) screening in cardiomyocytes identified miR-301a enriched specially in the neonatal cardiomyocytes from rats and mice. Overexpression of miR-301a in primary neonatal cardiomyocytes and H9C2 cells induced G₁/S transition of the cell cycle, promoted cellular proliferation, and protected cardiomyocytes against hypoxia-induced apoptosis. Adeno-associated virus (AAV)9-mediated cardiac delivery of miR-301a to the mice model with myocardial infarction (MI) dramatically promoted cardiac repair post-MI in vivo. Phosphatase and tensin homolog (PTEN)/phosphatidylinositol 3-kinase (PI3K)/AKT signaling pathway was confirmed to mediate miR-301a-induced cell proliferation in cardiomyocytes. Loss of function of PTEN mimicked the miR-301a-induced phenotype, while gain of function of PTEN attenuated the miR-301a-induced cell proliferation in cardiomyocytes. Application of RG7440, a small molecule inhibitor of AKT, blocked the function of miR-301a in cardiomyocytes. The current study revealed a miRNA signaling in inducing the cell cycle reentry of cardiomyocytes in the injured heart, and it demonstrated the miR-301a/PTEN/AKT signaling as a potential therapeutic target to reconstitute lost cardiomyocytes in mammals.

Keywords: PTEN; cardiac repair; cardiomyocytes; cell-cycle reentry; miR-301a; myocardial infarction.