PMID- 31152485 OWN - NLM STAT- MEDLINE DCOM- 20200923 LR - 20200923 IS - 1748-1716 (Electronic) IS - 1748-1708 (Linking) VI - 227 IP - 3 DP - 2019 Nov TI - MicroRNA-133 suppresses ZFHX3-dependent atrial remodelling and arrhythmia. PG - e13322 LID - 10.1111/apha.13322 [doi] AB - AIM: Atrial fibrillation (AF) is an important cause of morbidity and mortality in the modern world. Loss-of-function mutation in the zinc finger homeobox 3 gene (ZFHX3) is associated with increased risk of AF. MicroRNAs (miRNAs) participate in arrhythmogenesis, and thus miRNA modulators may be applicable as therapeutic modalities for AF. However, the altered miRNA profiles after ZFHX3 knockdown (KD) remain unclear. This study aimed to analyse the changes of miRNA expression in loss-of-function of ZFHX3 and the effect of miRNA modulation on atrial arrhythmias in this model. METHODS: We performed small RNA deep sequencing on ZFHX3-KD and control HL-1 mouse atrial myocytes. The effect of miRNAs on ZFHX3-dependent atrial arrhythmia was evaluated through in vitro and in vivo assays in mice. RESULTS: Among the differentially expressed miRNAs, 11 were down-regulated and 6 were up-regulated after ZFHX3 KD. Quantitative real-time PCR analysis confirmed that after ZFHX3 KD, miR-133a and miR-133b were significantly down-regulated, whereas miR-184 was the most significantly up-regulated. DIANA-miRPath analysis suggested that miR-133a/b down-regulation increases the targeted signalling of miR-133 (ie, adrenergic, Wnt/calcium and fibroblast growth factor receptor 1 signalling), which could contribute to pathological remodelling of cardiomyocytes. These results were confirmed through Western blotting. After transfection of miR-133a/b mimics in ZFHX3-KD cells, miR-133a/b levels increased, accompanied by the inhibition of their target signalling. Treatment with miR-133a/b mimics diminished ZFHX3 KD-induced atrial ectopy in mice. CONCLUSION: ZFHX3-KD promotes distinct miRNA expressional changes in atrial myocytes. MiR-133a/b mimics may reverse signalling of ZFHX3 KD-mediated cardiac remodelling and atrial arrhythmia. CI - (c) 2019 Scandinavian Physiological Society. Published by John Wiley & Sons Ltd. FAU - Cheng, Wan-Li AU - Cheng WL AUID- ORCID: 0000-0002-7887-2728 AD - Graduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan. FAU - Kao, Yu-Hsun AU - Kao YH AUID- ORCID: 0000-0001-8687-5091 AD - Graduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan. AD - Department of Medical Education and Research, Wan Fang Hospital, Taipei Medical University, Taipei, Taiwan. FAU - Chao, Tze-Fan AU - Chao TF AUID- ORCID: 0000-0002-6587-3094 AD - Division of Cardiology and Cardiovascular Research Center, Taipei Veterans General Hospital, Taipei, Taiwan. FAU - Lin, Yung-Kuo AU - Lin YK AUID- ORCID: 0000-0002-6674-5625 AD - Division of Cardiology, Department of Internal Medicine, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan. AD - Division of Cardiovascular Medicine, Department of Internal Medicine, Wan Fang Hospital, Taipei Medical University, Taipei, Taiwan. FAU - Chen, Shih-Ann AU - Chen SA AUID- ORCID: 0000-0001-9085-0823 AD - Division of Cardiology and Cardiovascular Research Center, Taipei Veterans General Hospital, Taipei, Taiwan. AD - School of Medicine, National Yang-Ming University, Taipei, Taiwan. FAU - Chen, Yi-Jen AU - Chen YJ AUID- ORCID: 0000-0001-7224-4491 AD - Graduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan. AD - Cardiovascular Research Center, Wan Fang Hospital, Taipei Medical University, Taipei, Taiwan. LA - eng GR - 104-wf-eva-01/Wan Fang Hospital, Taipei Medical University/International GR - 104swf01/Wan Fang Hospital, Taipei Medical University/International GR - 105swf09/Wan Fang Hospital, Taipei Medical University/International GR - 106-swf-02/Wan Fang Hospital, Taipei Medical University/International GR - MOST 105-2628-B-038-012-MY3/Ministry of Science and Technology, Taiwan/International GR - MOST 106-2811-B-038-013/Ministry of Science and Technology, Taiwan/International GR - MOST 107-2314-B-038-101-MY3/Ministry of Science and Technology, Taiwan/International GR - MOST 107-2811-B-038-507/Ministry of Science and Technology, Taiwan/International GR - NSC 102-2628-B-038-002-MY3/Ministry of Science and Technology, Taiwan/International PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20190618 PL - England TA - Acta Physiol (Oxf) JT - Acta physiologica (Oxford, England) JID - 101262545 RN - 0 (Homeodomain Proteins) RN - 0 (MicroRNAs) RN - 0 (Mirn133 microRNA, mouse) RN - 0 (Zfhx3 protein, mouse) RN - EC 7.2.2.10 (Calcium-Transporting ATPases) RN - SY7Q814VUP (Calcium) SB - IM CIN - Acta Physiol (Oxf). 2019 Nov;227(3):e13372. PMID: 31465613 MH - Animals MH - Arrhythmias, Cardiac MH - Atrial Remodeling/*physiology MH - Calcium/metabolism MH - Calcium-Transporting ATPases/metabolism MH - Down-Regulation MH - Gene Knockdown Techniques MH - Heart Atria/cytology MH - Homeodomain Proteins/genetics/*metabolism MH - Mice MH - MicroRNAs/genetics/*metabolism MH - Myocytes, Cardiac/*metabolism MH - Sarcoplasmic Reticulum MH - Up-Regulation OTO - NOTNLM OT - ZFHX3 OT - MicroRNA-133 OT - Wnt/calcium signalling OT - atrial ectopy OT - cardiac remodelling OT - connexin43 EDAT- 2019/06/04 06:00 MHDA- 2020/09/24 06:00 CRDT- 2019/06/02 06:00 PHST- 2018/10/19 00:00 [received] PHST- 2019/05/16 00:00 [revised] PHST- 2019/05/28 00:00 [accepted] PHST- 2019/06/04 06:00 [pubmed] PHST- 2020/09/24 06:00 [medline] PHST- 2019/06/02 06:00 [entrez] AID - 10.1111/apha.13322 [doi] PST - ppublish SO - Acta Physiol (Oxf). 2019 Nov;227(3):e13322. doi: 10.1111/apha.13322. Epub 2019 Jun 18.