PMID- 30287867 OWN - NLM STAT- MEDLINE DCOM- 20190305 LR - 20190305 IS - 1476-5462 (Electronic) IS - 0969-7128 (Linking) VI - 25 IP - 8 DP - 2018 Dec TI - Long noncoding RNA Meg3 regulates cardiomyocyte apoptosis in myocardial infarction. PG - 511-523 LID - 10.1038/s41434-018-0045-4 [doi] AB - Myocardial infarction (MI), with a major process of cardiomyocyte death, remains a leading cause of morbidity and mortality worldwide. To date, it has been shown that lncRNAs play important roles in cardiovascular pathology. However, the detailed studies on lncRNAs regulating cardiomyocyte death in myocardial infarction are still limited. In this study, we found a progressively upregulated expression of Meg3 in mouse injured heart after MI. Gain-of-function and loss-of-function approaches further revealed pro-apoptotic functions of Meg3 in rodent cardiomyocytes. Moreover, Meg3 was directly upregulated by p53 in hypoxic condition, and involved in apoptotic regulation via its direct binding with RNA-binding protein FUS (fused in sarcoma). Afterwards, adult MI mice that underwent intramyocardial injection with adeno-associated virus serotype 9 (AAV9) system carrying Meg3 shRNA showed a significant improvement of cardiac function. Moreover, we also found that MEG3 was increased in clinical heart failure samples, and had conservatively pro-apoptotic function in human cardiomyocytes that were differentiated from the human embryonic stem cells. Together, these results indicate that p53-induced Meg3-FUS complex plays an important role in cardiomyocyte apoptosis post-MI, and its specific knockdown in cardiomyocytes with AAV9 system represents a promising method to treat MI for preclinical investigation. FAU - Wu, Hongchun AU - Wu H AD - Institute for Cardiovascular Science & Department of Cardiovascular Surgery of the First Affiliated Hospital, Medical College, Soochow University, Suzhou, 215000, China. AD - Key Laboratory of Stem Cells and Biomedical Materials of Jiangsu Province and Chinese Ministry of Science and Technology, Medical College, Soochow University, Suzhou, 215000, China. FAU - Zhao, Zhen-Ao AU - Zhao ZA AD - Institute for Cardiovascular Science & Department of Cardiovascular Surgery of the First Affiliated Hospital, Medical College, Soochow University, Suzhou, 215000, China. AD - Key Laboratory of Stem Cells and Biomedical Materials of Jiangsu Province and Chinese Ministry of Science and Technology, Medical College, Soochow University, Suzhou, 215000, China. FAU - Liu, Junwei AU - Liu J AD - Department of Cardiovascular Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China. FAU - Hao, Kaili AU - Hao K AD - Institute for Cardiovascular Science & Department of Cardiovascular Surgery of the First Affiliated Hospital, Medical College, Soochow University, Suzhou, 215000, China. AD - Key Laboratory of Stem Cells and Biomedical Materials of Jiangsu Province and Chinese Ministry of Science and Technology, Medical College, Soochow University, Suzhou, 215000, China. FAU - Yu, You AU - Yu Y AD - Institute for Cardiovascular Science & Department of Cardiovascular Surgery of the First Affiliated Hospital, Medical College, Soochow University, Suzhou, 215000, China. AD - Key Laboratory of Stem Cells and Biomedical Materials of Jiangsu Province and Chinese Ministry of Science and Technology, Medical College, Soochow University, Suzhou, 215000, China. FAU - Han, Xinglong AU - Han X AD - Institute for Cardiovascular Science & Department of Cardiovascular Surgery of the First Affiliated Hospital, Medical College, Soochow University, Suzhou, 215000, China. AD - Key Laboratory of Stem Cells and Biomedical Materials of Jiangsu Province and Chinese Ministry of Science and Technology, Medical College, Soochow University, Suzhou, 215000, China. FAU - Li, Jingjing AU - Li J AD - Institute for Cardiovascular Science & Department of Cardiovascular Surgery of the First Affiliated Hospital, Medical College, Soochow University, Suzhou, 215000, China. AD - Key Laboratory of Stem Cells and Biomedical Materials of Jiangsu Province and Chinese Ministry of Science and Technology, Medical College, Soochow University, Suzhou, 215000, China. FAU - Wang, Yixuan AU - Wang Y AD - Department of Cardiovascular Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China. FAU - Lei, Wei AU - Lei W AD - Institute for Cardiovascular Science & Department of Cardiovascular Surgery of the First Affiliated Hospital, Medical College, Soochow University, Suzhou, 215000, China. AD - Key Laboratory of Stem Cells and Biomedical Materials of Jiangsu Province and Chinese Ministry of Science and Technology, Medical College, Soochow University, Suzhou, 215000, China. FAU - Dong, Nianguo AU - Dong N AD - Department of Cardiovascular Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China. FAU - Shen, Zhenya AU - Shen Z AD - Institute for Cardiovascular Science & Department of Cardiovascular Surgery of the First Affiliated Hospital, Medical College, Soochow University, Suzhou, 215000, China. AD - Key Laboratory of Stem Cells and Biomedical Materials of Jiangsu Province and Chinese Ministry of Science and Technology, Medical College, Soochow University, Suzhou, 215000, China. FAU - Hu, Shijun AU - Hu S AD - Institute for Cardiovascular Science & Department of Cardiovascular Surgery of the First Affiliated Hospital, Medical College, Soochow University, Suzhou, 215000, China. shijunhu@suda.edu.cn. AD - Key Laboratory of Stem Cells and Biomedical Materials of Jiangsu Province and Chinese Ministry of Science and Technology, Medical College, Soochow University, Suzhou, 215000, China. shijunhu@suda.edu.cn. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20181004 PL - England TA - Gene Ther JT - Gene therapy JID - 9421525 RN - 0 (FUS protein, mouse) RN - 0 (MEG3 non-coding RNA, mouse) RN - 0 (RNA, Long Noncoding) RN - 0 (RNA-Binding Protein FUS) RN - 0 (Tumor Suppressor Protein p53) SB - IM MH - Animals MH - *Apoptosis MH - Cell Hypoxia MH - Cells, Cultured MH - Dependovirus/genetics MH - Female MH - Humans MH - Mice MH - Myocardial Infarction/*genetics/metabolism/therapy MH - Myocytes, Cardiac/*metabolism MH - RNA, Long Noncoding/*genetics/metabolism MH - RNA-Binding Protein FUS/metabolism MH - RNAi Therapeutics/*methods MH - Tumor Suppressor Protein p53/metabolism EDAT- 2018/10/06 06:00 MHDA- 2019/03/06 06:00 CRDT- 2018/10/06 06:00 PHST- 2018/05/19 00:00 [received] PHST- 2018/09/21 00:00 [accepted] PHST- 2018/07/07 00:00 [revised] PHST- 2018/10/06 06:00 [pubmed] PHST- 2019/03/06 06:00 [medline] PHST- 2018/10/06 06:00 [entrez] AID - 10.1038/s41434-018-0045-4 [pii] AID - 10.1038/s41434-018-0045-4 [doi] PST - ppublish SO - Gene Ther. 2018 Dec;25(8):511-523. doi: 10.1038/s41434-018-0045-4. Epub 2018 Oct 4.