title: β-arrestin2/miR-155/GSK3β regulates transition of 5'-azacytizine-induced Sca-1-positive cells to cardiomyocytes.
abstract: Stem-cell antigen 1-positive (Sca-1+) cardiac stem cells (CSCs), a vital kind of CSCs in humans, promote cardiac repair in vivo and can differentiate to cardiomyocytes with 5'-azacytizine treatment in vitro. However, the underlying molecular mechanisms are unknown. β-arrestin2 is an important scaffold protein and highly expressed in the heart. To explore the function of β-arrestin2 in Sca-1+ CSC differentiation, we used β-arrestin2-knockout mice and overexpression strategies. Real-time PCR revealed that β-arrestin2 promoted 5'-azacytizine-induced Sca-1+ CSC differentiation in vitro. Because the microRNA 155 (miR-155) may regulate β-arrestin2 expression, we detected its role and relationship with β-arrestin2 and glycogen synthase kinase 3 (GSK3β), another probable target of miR-155. Real-time PCR revealed that miR-155, inhibited by β-arrestin2, impaired 5'-azacytizine-induced Sca-1+ CSC differentiation. On luciferase report assay, miR-155 could inhibit the activity of β-arrestin2 and GSK3β, which suggests a loop pathway between miR-155 and β-arrestin2. Furthermore, β-arrestin2-knockout inhibited the activity of GSK3β. Akt, the upstream inhibitor of GSK3β, was inhibited in β-arrestin2-Knockout mice, so the activity of GSK3β was regulated by β-arrestin2 not Akt. We transplanted Sca-1+ CSCs from β-arrestin2-knockout mice to mice with myocardial infarction and found similar protective functions as in wild-type mice but impaired arterial elastance. Furthermore, low level of β-arrestin2 agreed with decreased phosphorylation of AKT and increased phophorylation of GSK3β, similar to in vitro findings. The β-arrestin2/miR-155/GSK3β pathway may be a new mechanism with implications for treatment of heart disease.
authors: Institute of Developmental Biology, School of Life Science, Shandong University, Jinan, China; Department of Internal Medicine, College of Medicine, East Tennessee State University, Johnson City, TN, USA.
authors: Jing
authors: J
authors: Zhao
authors: Yimin
authors: Y
authors: Feng
authors: Hui
authors: H
authors: Yan
authors: Yangchao
authors: Y
authors: Chen
authors: Jinlan
authors: J
authors: Wang
authors: Balvin
authors: B
authors: Chua
authors: Charles
authors: C
authors: Stuart
authors: Deling
authors: D
authors: Yin
mesh_terms: D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology; D019390:Arrestins / Q000502:physiology*; D001374:Azacitidine / Q000494:pharmacology*; D002454:Cell Differentiation / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D005455:Fluorescent Antibody Technique; D038362:Glycogen Synthase Kinase 3 / Q000235:genetics / Q000378:metabolism*; D000071679:Glycogen Synthase Kinase 3 beta; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D035683:MicroRNAs / Q000235:genetics*; D015428:Myocardial Reperfusion Injury / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D032383:Myocytes, Cardiac / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D020754:Spinocerebellar Ataxias / Q000378:metabolism*; D000071557:beta-Arrestins
chemical_list: D000964:Antimetabolites, Antineoplastic; D019390:Arrestins; D035683:MicroRNAs; C532623:Mirn155 microRNA, mouse; D012333:RNA, Messenger; D000071557:beta-Arrestins; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; C000605507:Gsk3b protein, mouse; D038362:Glycogen Synthase Kinase 3; D001374:Azacitidine
keywords: GSK3β; MiR-155; cardiac stem cells; cardiomyocytes; stem cell antigen-1; β-arrestin2