title: Syndecan-4 signalling inhibits apoptosis and controls NFAT activity during myocardial damage and remodelling.
abstract: OBJECTIVE
  Myocardial infarction (MI) results in acute impairment of left ventricular (LV) function through the initial development of cardiomyocyte death and subsequent progression of LV remodelling. The expression of syndecan-4 (Sdc4), a transmembrane proteoglycan, is up-regulated after MI, but its function in the heart remains unknown. Here, we characterize the effects of Sdc4 deficiency in murine myocardial ischaemia and permanent infarction.
  
  
  RESULTS
  Targeted deletion of Sdc4 (Sdc4(-/-)) leads to increased myocardial damage after ischaemic-reperfusion injury due to enhanced cardiomyocyte apoptosis associated with reduced activation of extracellular signal-regulated kinase in cardiomyocytes in vitro and in vivo. After ischaemic-reperfusion injury and permanent infarction, we observed an increase in cardiomyocyte area, nuclear translocation of nuclear factor of activated T cells (NFAT), and transcription of the NFAT target rcan1.4 in wild-type mice. NFAT pathway activation was enhanced in Sdc4(-/-) mice. In line with the in vivo data, NFAT activation and hypertrophy occurs in isolated cardiomyocytes with reduced Sdc4 expression during phenylephrine stimulation in vitro. Despite the initially increased myocardial damage, echocardiography revealed improved LV geometry and function in Sdc4(-/-) mice 7 days after MI.
  
  
  CONCLUSIONS
  Interception of the Sdc4 pathway enhances infarct expansion and hypertrophic remodelling during early infarct healing in ischaemic-reperfusion injury and permanent infarction mouse models and exerts net beneficial effects on LV function.
authors.affiliation: Department of Anesthesiology and Intensive Care Medicine, Hannover Medical School, Carl-Neuberg Str. 1, 30625 Hannover, Germany.
authors.forename: Frank
authors.initials: F
authors.lastname: Echtermeyer
authors.forename: Thomas
authors.initials: T
authors.lastname: Harendza
authors.forename: Svenja
authors.initials: S
authors.lastname: Hubrich
authors.forename: Anika
authors.initials: A
authors.lastname: Lorenz
authors.forename: Christine
authors.initials: C
authors.lastname: Herzog
authors.forename: Martin
authors.initials: M
authors.lastname: Mueller
authors.forename: Martina
authors.initials: M
authors.lastname: Schmitz
authors.forename: Andrea
authors.initials: A
authors.lastname: Grund
authors.forename: Jan
authors.initials: J
authors.lastname: Larmann
authors.forename: Jörg
authors.initials: J
authors.lastname: Stypmann
authors.forename: Bernhard
authors.initials: B
authors.lastname: Schieffer
authors.forename: Ralf
authors.initials: R
authors.lastname: Lichtinghagen
authors.forename: Denise
authors.initials: D
authors.lastname: Hilfiker-Kleiner
authors.forename: Kai C
authors.initials: KC
authors.lastname: Wollert
authors.forename: Jörg
authors.initials: J
authors.lastname: Heineke
authors.forename: Gregor
authors.initials: G
authors.lastname: Theilmeier
mesh_terms: D000818:Animals; D017209:Apoptosis; D006332:Cardiomegaly / Q000209:etiology; D002478:Cells, Cultured; D051379:Mice; D008810:Mice, Inbred C57BL; D009203:Myocardial Infarction / Q000473:pathology; D015428:Myocardial Reperfusion Injury / Q000517:prevention & control*; D009206:Myocardium / Q000473:pathology*; D032383:Myocytes, Cardiac / Q000473:pathology; D050778:NFATC Transcription Factors / Q000502:physiology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000502:physiology*; D053671:Syndecan-4 / Q000172:deficiency / Q000502:physiology*; D016277:Ventricular Function, Left; D020257:Ventricular Remodeling; D048051:p38 Mitogen-Activated Protein Kinases / Q000502:physiology
chemical_list: D050778:NFATC Transcription Factors; D053671:Syndecan-4; D048051:p38 Mitogen-Activated Protein Kinases