title: GSK-3β Inhibitor CHIR-99021 Promotes Proliferation Through Upregulating β-Catenin in Neonatal Atrial Human Cardiomyocytes.
abstract: BACKGROUND
  The renewal capacity of neonate human cardiomyocytes provides an opportunity to manipulate endogenous cardiogenic mechanisms for supplementing the loss of cardiomyocytes caused by myocardial infarction or other cardiac diseases. GSK-3β inhibitors have been recently shown to promote cardiomyocyte proliferation in rats and mice, thus may be ideal candidates for inducing human cardiomyocyte proliferation.
  
  
  METHODS
  Human cardiomyocytes were isolated from right atrial specimens obtained during routine surgery for ventricle septal defect and cultured with either GSK-3β inhibitor (CHIR-99021) or β-catenin inhibitor (IWR-1). Immunocytochemistry was performed to visualize 5-ethynyl-2'-deoxyuridine (EdU)-positive or Ki67-positive cardiomyocytes, indicative of proliferative cardiomyocytes.
  
  
  RESULTS
  GSK-3β inhibitor significantly increased β-catenin accumulation in cell nucleus, whereas β-catenin inhibitor significantly reduced β-catenin accumulation in cell plasma. In parallel, GSK-3β inhibitor increased EdU-positive and Ki67-positive cardiomyocytes, whereas β-catenin inhibitor decreased EdU-positive and Ki67-positive cardiomyocytes.
  
  
  CONCLUSIONS
  These results indicate that GSK-3β inhibitor can promote human atrial cardiomyocyte proliferation. Although it remains to be determined whether the observations in atrial myocytes could be directly applicable to ventricular myocytes, the current findings imply that Wnt/β-catenin pathway may be a valuable pathway for manipulating endogenous human heart regeneration.
authors: *Department of Thoracic and Cardiovascular Surgery, Shanghai Children's Medical Center, Shanghai Jiaotong University School of Medicine, Shanghai, China; †Shanghai Institute of Pediatric Congenital Heart Diseases, Shanghai Children's Medical Center, Shanghai Jiaotong University School of Medicine, Shanghai, China; and ‡Institute of Pediatric Translational Medicine, Shanghai Children's Medical Center, Shanghai Jiaotong University School of Medicine, Shanghai, China.
authors: Shoubao
authors: S
authors: Wang
authors: Lincai
authors: L
authors: Ye
authors: Minghui
authors: M
authors: Li
authors: Jinfen
authors: J
authors: Liu
authors: Chuan
authors: C
authors: Jiang
authors: Haifa
authors: H
authors: Hong
authors: Hongbin
authors: H
authors: Zhu
authors: Yanjun
authors: Y
authors: Sun
mesh_terms: D049109:Cell Proliferation / Q000187:drug effects* / Q000502:physiology; D002478:Cells, Cultured; D005260:Female; D000071679:Glycogen Synthase Kinase 3 beta / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006325:Heart Atria / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008297:Male; D032383:Myocytes, Cardiac / Q000187:drug effects* / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology*; D011743:Pyrimidines / Q000494:pharmacology*; D015854:Up-Regulation / Q000187:drug effects* / Q000502:physiology; D051176:beta Catenin / Q000096:biosynthesis*
chemical_list: C495270:CTNNB1 protein, human; C473711:Chir 99021; D047428:Protein Kinase Inhibitors; D011725:Pyridines; D011743:Pyrimidines; D051176:beta Catenin; D000071679:Glycogen Synthase Kinase 3 beta