title: mir-17-92 cluster is required for and sufficient to induce cardiomyocyte proliferation in postnatal and adult hearts.
abstract: BACKGROUND
  Cardiomyocytes in adult mammalian hearts are terminally differentiated cells that have exited from the cell cycle and lost most of their proliferative capacity. Death of mature cardiomyocytes in pathological cardiac conditions and the lack of regeneration capacity of adult hearts are primary causes of heart failure and mortality. However, how cardiomyocyte proliferation in postnatal and adult hearts becomes suppressed remains largely unknown. The miR-17-92 cluster was initially identified as a human oncogene that promotes cell proliferation. However, its role in the heart remains unknown.
  
  
  OBJECTIVE
  To test the hypothesis that miR-17-92 participates in the regulation of cardiomyocyte proliferation in postnatal and adult hearts.
  
  
  RESULTS
  We deleted miR-17-92 cluster from embryonic and postnatal mouse hearts and demonstrated that miR-17-92 is required for cardiomyocyte proliferation in the heart. Transgenic overexpression of miR-17-92 in cardiomyocytes is sufficient to induce cardiomyocyte proliferation in embryonic, postnatal, and adult hearts. Moreover, overexpression of miR-17-92 in adult cardiomyocytes protects the heart from myocardial infarction-induced injury. Similarly, we found that members of miR-17-92 cluster, miR-19 in particular, are required for and sufficient to induce cardiomyocyte proliferation in vitro. We identified phosphatase and tensin homolog, a tumor suppressor, as an miR-17-92 target to mediate the function of miR-17-92 in cardiomyocyte proliferation.
  
  
  CONCLUSIONS
  Our studies therefore identify miR-17-92 as a critical regulator of cardiomyocyte proliferation, and suggest this cluster of microRNAs could become therapeutic targets for cardiac repair and heart regeneration.
authors.affiliation: Department of Cardiology, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Jinghai
authors.initials: J
authors.lastname: Chen
authors.forename: Zhan-Peng
authors.initials: ZP
authors.lastname: Huang
authors.forename: Hee Young
authors.initials: HY
authors.lastname: Seok
authors.forename: Jian
authors.initials: J
authors.lastname: Ding
authors.forename: Masaharu
authors.initials: M
authors.lastname: Kataoka
authors.forename: Zheng
authors.initials: Z
authors.lastname: Zhang
authors.forename: Xiaoyun
authors.initials: X
authors.lastname: Hu
authors.forename: Gang
authors.initials: G
authors.lastname: Wang
authors.forename: Zhiqiang
authors.initials: Z
authors.lastname: Lin
authors.forename: Si
authors.initials: S
authors.lastname: Wang
authors.forename: Willam T
authors.initials: WT
authors.lastname: Pu
authors.forename: Ronglih
authors.initials: R
authors.lastname: Liao
authors.forename: Da-Zhi
authors.initials: DZ
authors.lastname: Wang
mesh_terms: D000367:Age Factors; D000818:Animals; D000831:Animals, Newborn; D049109:Cell Proliferation; D002478:Cells, Cultured; D004195:Disease Models, Animal; D018507:Gene Expression Regulation, Developmental; D006321:Heart / Q000196:embryology*; D000072576:Homeobox Protein Nkx-2.5; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D009203:Myocardial Infarction / Q000000981:diagnostic imaging / Q000235:genetics / Q000378:metabolism* / Q000517:prevention & control; D032383:Myocytes, Cardiac / Q000378:metabolism* / Q000473:pathology; D051059:PTEN Phosphohydrolase / Q000235:genetics / Q000378:metabolism; D034622:RNA Interference; D051381:Rats; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D014162:Transfection; D014463:Ultrasonography
chemical_list: D000072576:Homeobox Protein Nkx-2.5; D018398:Homeodomain Proteins; C575895:MIRN17-92 microRNA, mouse; D035683:MicroRNAs; C484469:Nkx2-5 protein, mouse; D014157:Transcription Factors; D051059:PTEN Phosphohydrolase; C487757:Pten protein, mouse
keywords: PTEN; cardiomyocyte proliferation; cell cycle; heart disease; miR-17–92; myocardial infarction