title: DYRK2 negatively regulates cardiomyocyte growth by mediating repressor function of GSK-3β on eIF2Bε.
abstract: BACKGROUND
  A prerequisite of hypertrophic response of the myocardium is an increase in protein synthesis. A central regulator of translation initiation is Eukaryotic initiation factor 2B (eIF2B). Here we assessed the hypothesis that regulation of protein synthesis via eIF2Bε is essential to cardiac hypertrophic response in vivo.
  
  
  METHODS
  Two transgenic mouse lines were generated with cardiac restricted overexpression of eIF2Bε or its mutant eIF2Bε-eIFS(535)A, which cannot be inactivated by phosphorylation through GSK-3β.
  
  
  RESULTS
  (1) Under baseline conditions eIF2Bε transgenic mice showed no difference in cardiac phenotype compared to wild type, whereas in the mutant eIF2Bε-S(535)A an increase in LV/tibia length (7.5 ± 0.4 mg/mm vs. 6.2 ± 0.2 mg/mm, p<0.001) and cardiomyocyte cross sectional area (13004 ± 570 vs. 10843 ± 347 RU, p<0.01) was observed. (2) Cardiac overexpression of eIF2Bε did not change the response of the heart to pathologic stress induced by chronic isoproterenol treatment. (3) Cardiac overexpression of the eIF2Bε transgene was followed by overexpression of DYRK2 which is known to prime the inhibitory action of GSK-3β on eIF2Bε, while DYRK1A and GSK-3β itself were not increased. (4) In C57BL/6 mice after 48 h of isoproterenol-stimulation or aortic banding, eIF2Bε was increased and DYRK2 was concomitantly decreased. (5) In line with these in vivo findings, siRNA knockdown of DYRK2 in cultured cardiomyocytes resulted in decreased levels of p(S535)- eIF2Bε, (6) whereas adenoviral induced overexpression of DYRK2 was accompanied by clearly increased phosphorylation of eIF2Bε, indicating a coordinated response pattern (7) Adenoviral induced overexpression of DYRK2 leads to significantly reduced cardiomyocyte size and diminishes hypertrophic response to adrenergic stimulation.
  
  
  CONCLUSIONS
  The interaction of GSK-3β and its priming kinase DYRK2 regulate the activity of eIF2Bε in cardiac myocytes. DYRK2 is a novel negative regulator of cardiomyocyte growth. DYRK2 could serve as a therapeutic option to regulate myocardial growth.
authors.affiliation: Internal Medicine III, University Hospital Heidelberg and DZHK (German Center for Cardiovascular Research), Heidelberg, Germany.
authors.forename: Celine S
authors.initials: CS
authors.lastname: Weiss
authors.forename: Marco M
authors.initials: MM
authors.lastname: Ochs
authors.forename: Marco
authors.initials: M
authors.lastname: Hagenmueller
authors.forename: Marcus R
authors.initials: MR
authors.lastname: Streit
authors.forename: Pratima
authors.initials: P
authors.lastname: Malekar
authors.forename: Johannes H
authors.initials: JH
authors.lastname: Riffel
authors.forename: Sebastian J
authors.initials: SJ
authors.lastname: Buss
authors.forename: Karl H
authors.initials: KH
authors.lastname: Weiss
authors.forename: Junichi
authors.initials: J
authors.lastname: Sadoshima
authors.forename: Hugo A
authors.initials: HA
authors.lastname: Katus
authors.forename: Stefan E
authors.initials: SE
authors.lastname: Hardt
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D004452:Echocardiography; D020717:Eukaryotic Initiation Factor-2B / Q000235:genetics / Q000378:metabolism*; D038362:Glycogen Synthase Kinase 3 / Q000235:genetics / Q000378:metabolism*; D000071679:Glycogen Synthase Kinase 3 beta; D017379:Hypertrophy, Left Ventricular / Q000235:genetics / Q000378:metabolism; D047468:Immunoprecipitation; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D032383:Myocytes, Cardiac / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D011505:Protein-Tyrosine Kinases / Q000235:genetics / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D000097603:Dyrk Kinases
chemical_list: D020717:Eukaryotic Initiation Factor-2B; D038362:Glycogen Synthase Kinase 3; D000071679:Glycogen Synthase Kinase 3 beta; D017346:Protein Serine-Threonine Kinases; D011505:Protein-Tyrosine Kinases; D034741:RNA, Small Interfering; D000097603:Dyrk Kinases; C000605507:Gsk3b protein, mouse
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