title: The H19 long noncoding RNA is a novel negative regulator of cardiomyocyte hypertrophy.
abstract: The H19 lncRNA, a highly abundant and conserved imprinted gene, has been implicated in many essential biological processes and diseases. However, the function of H19 in the heart remains unknown. In this study, we investigated the function and underlying mechanism of H19 in regulating cardiomyocyte hypertrophy.
  
  
  
  We first detected the expression of H19 and its encoded miR-675 in both normal and diseased hearts and verified their up-regulations in pathological cardiac hypertrophy and heart failure. Adenovirus-mediated expression and a siRNA-mediated silence of H19 showed that H19 overexpression reduced cell size both at baseline and in response to phenylephrine, whereas knock-down of H19 induced cardiomyocyte hypertrophy. Overexpression or knock-down of miR-675 in cardiomyocytes demonstrated that miR-675 also inhibited cardiomyocyte hypertrophy. Moreover, inhibition of miR-675 reversed the reduction of cardiomyocyte size in H19-overexpressing cardiomyocytes, while infection with an adenovirus carrying H19 fragment without pre-miR-675 (H19-Tru) or with mutant sequences of pre-miR-675 (H19-Mut) failed to reduce cardiomyocyte size, indicating that miR-675 mediated the inhibitory effect of H19 on cardiomyocyte hypertrophy. We also identified that CaMKIIδ was a direct target of miR-675 and partially mediated the effect of H19 on cardiomyocyte hypertrophy. Furthermore, in vivo silencing of miR-675 using a specific antagomir in a pressure overload-induced mouse model of heart failure increased cardiac CaMKIIδ expression and exacerbated cardiac hypertrophy.
  
  
  
  These findings reveal a novel function of H19-miR-675 axis targeting CaMKIIδ as a negative regulator of cardiac hypertrophy, suggesting its potential therapeutic role in cardiac diseases.
authors.affiliation: State Key Laboratory of Proteomics, Collaborative Innovation Center for Cardiovascular Disorders, Genetic Laboratory of Development and Disease, Institute of Biotechnology, 20 Dongdajie, Beijing 100071, China.
authors.forename: Lantao
authors.initials: L
authors.lastname: Liu
authors.affiliation: Institute of Vascular Medicine, Peking University Third Hospital and Key Laboratory of Molecular Cardiovascular Sciences, Ministry of Education, Key Laboratory of Cardiovascular Molecular Biology and Regulatory Peptides, Ministry of Health, 49 Huayuan-Bei Road, Beijing 100191, China.
authors.forename: Xiangbo
authors.initials: X
authors.lastname: An
authors.affiliation: State Key Laboratory of Proteomics, Collaborative Innovation Center for Cardiovascular Disorders, Genetic Laboratory of Development and Disease, Institute of Biotechnology, 20 Dongdajie, Beijing 100071, China.
authors.forename: Zhenhua
authors.initials: Z
authors.lastname: Li
authors.affiliation: Institute of Vascular Medicine, Peking University Third Hospital and Key Laboratory of Molecular Cardiovascular Sciences, Ministry of Education, Key Laboratory of Cardiovascular Molecular Biology and Regulatory Peptides, Ministry of Health, 49 Huayuan-Bei Road, Beijing 100191, China.
authors.forename: Yao
authors.initials: Y
authors.lastname: Song
authors.affiliation: Department of Cardiology, Beijing Anzhen Hospital, Capital Medical University, National Clinical Research Center for Cardiovascular Diseases, Beijing, China.
authors.forename: Linling
authors.initials: L
authors.lastname: Li
authors.affiliation: Department of Cardiology, Beijing Anzhen Hospital, Capital Medical University, National Clinical Research Center for Cardiovascular Diseases, Beijing, China.
authors.forename: Song
authors.initials: S
authors.lastname: Zuo
authors.affiliation: Department of Cardiology, Beijing Anzhen Hospital, Capital Medical University, National Clinical Research Center for Cardiovascular Diseases, Beijing, China.
authors.forename: Nian
authors.initials: N
authors.lastname: Liu
authors.affiliation: State Key Laboratory of Proteomics, Collaborative Innovation Center for Cardiovascular Disorders, Genetic Laboratory of Development and Disease, Institute of Biotechnology, 20 Dongdajie, Beijing 100071, China.
authors.forename: Guan
authors.initials: G
authors.lastname: Yang
authors.affiliation: State Key Laboratory of Proteomics, Collaborative Innovation Center for Cardiovascular Disorders, Genetic Laboratory of Development and Disease, Institute of Biotechnology, 20 Dongdajie, Beijing 100071, China.
authors.forename: Haijing
authors.initials: H
authors.lastname: Wang
authors.affiliation: State Key Laboratory of Proteomics, Collaborative Innovation Center for Cardiovascular Disorders, Genetic Laboratory of Development and Disease, Institute of Biotechnology, 20 Dongdajie, Beijing 100071, China.
authors.forename: Xuan
authors.initials: X
authors.lastname: Cheng
authors.affiliation: Institute of Vascular Medicine, Peking University Third Hospital and Key Laboratory of Molecular Cardiovascular Sciences, Ministry of Education, Key Laboratory of Cardiovascular Molecular Biology and Regulatory Peptides, Ministry of Health, 49 Huayuan-Bei Road, Beijing 100191, China yangx@bmi.ac.cn wangjian7773@126.com zhangyy@bjmu.edu.cn.
authors.forename: Youyi
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: State Key Laboratory of Proteomics, Collaborative Innovation Center for Cardiovascular Disorders, Genetic Laboratory of Development and Disease, Institute of Biotechnology, 20 Dongdajie, Beijing 100071, China yangx@bmi.ac.cn wangjian7773@126.com zhangyy@bjmu.edu.cn.
authors.forename: Xiao
authors.initials: X
authors.lastname: Yang
authors.affiliation: State Key Laboratory of Proteomics, Collaborative Innovation Center for Cardiovascular Disorders, Genetic Laboratory of Development and Disease, Institute of Biotechnology, 20 Dongdajie, Beijing 100071, China yangx@bmi.ac.cn wangjian7773@126.com zhangyy@bjmu.edu.cn.
authors.forename: Jian
authors.initials: J
authors.lastname: Wang
mesh_terms: D020413:3' Untranslated Regions; D000818:Animals; D001665:Binding Sites; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2 / Q000235:genetics / Q000378:metabolism; D006332:Cardiomegaly / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D004195:Disease Models, Animal; D005786:Gene Expression Regulation; D057809:HEK293 Cells; D006333:Heart Failure / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D006801:Humans; D008297:Male; D008810:Mice, Inbred C57BL; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism; D009154:Mutation; D032383:Myocytes, Cardiac / Q000378:metabolism* / Q000473:pathology; D034622:RNA Interference; D062085:RNA, Long Noncoding / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D014162:Transfection
chemical_list: D020413:3' Untranslated Regions; C094335:H19 long non-coding RNA; C574758:MIRN675 microRNA, mouse; D035683:MicroRNAs; D062085:RNA, Long Noncoding; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; C517673:Camk2d protein, mouse
keywords: CaMKIIδ; Cardiac hypertrophy; H19; Long noncoding RNA; miR-675