Cardiac‐specific overexpression of miR‐122 induces mitochondria‐dependent cardiomyocyte apoptosis and promotes heart failure by inhibiting Hand2

• Published in: Journal of cellular and molecular medicine Vol. 25; no. 11; pp. 5326 - 5334
• Main Authors: Shi, Yajuan, Zhang, Zhi, Yin, Qiqi, Fu, Chen, Barszczyk, Andrew, Zhang, Xiaofu, Wang, Jiabing, Yang, Deye
• Format: Journal Article
• Language: English
• Published: England John Wiley & Sons, Inc 01-06-2021; John Wiley and Sons Inc
• Subjects: Animals; Apoptosis; Basic Helix-Loop-Helix Transcription Factors - genetics; Basic Helix-Loop-Helix Transcription Factors - metabolism; Binding sites; Cardiomyocytes; Congestive heart failure; Dynamin; Echocardiography; Flow cytometry; Gene expression; Gene Expression Regulation; Hand2; Heart attacks; Heart failure; Heart Failure - etiology; Heart Failure - metabolism; Heart Failure - pathology; Humans; Mice; Mice, Transgenic; MicroRNAs; MicroRNAs - genetics; miRNA; miR‐122; Mitochondria; Mitochondria, Heart - genetics; Mitochondria, Heart - metabolism; Mitochondria, Heart - pathology; Mitochondrial Dynamics; mitochondrial fission protein Drp1; mitochondria‐dependent apoptosis; Morphology; Myocytes, Cardiac - metabolism; Myocytes, Cardiac - pathology; Original; Protein expression; Proteins; Signal Transduction; Transcription factors; Transgenic mice; heart failure; mitochondria-dependent apoptosis; mitochondrial fission protein Drp1; miR-122; Hand2
• ISSN: 1582-1838; 1582-4934; 1582-4934
• DOI: 10.1111/jcmm.16544

MicroRNA‐122 (miR‐122) is one of several microRNAs elevated in heart failure patients. To investigate the potential role and mechanism of miR‐122 in heart failure, we constructed a transgenic mouse overexpressing miR‐122 in the heart. This mouse exhibited cardiac dysfunction (as assessed by transthoracic echocardiography), morphological abnormalities of the heart and cardiomyocyte apoptosis characteristic of heart failure. Mechanistically, we identified the Hand2 transcription factor as a direct target of miR‐122 using a dual‐luciferase reporter assay. In Tg‐miR‐122 mice and H9C2 cells with miR‐122 mimics, we detected apoptosis and increased expression of dynamin‐related protein‐1 (Drp1). This effect was blocked with prior knockdown of Hand2 in vitro. Our work suggests that miR‐122 causes cardiomyocyte apoptosis by inhibiting Hand2 and consequently increasing Drp1‐mediated mitochondrial fission. Such a mechanism likely contributes to heart failure and so modulating this pathway could be therapeutically valuable against heart failure.