title: Expression of fibulin-6 in failing hearts and its role for cardiac fibroblast migration.
abstract: OBJECTIVE
  The cardiac extracellular matrix (ECM) undergoes a dynamic transition following myocardial infarction. Fibulin-6 is expressed in cell junctions particularly in tissues subjected to significant mechanical stress. Fibulin-6 deficiency results in defective cell migration in nematodes and early embryonic lethality in mice. The role of fibulin-6 in healthy and failing myocardium is unknown. We have examined the expression and distribution pattern of fibulin-6 during myocardial remodelling (MR) and detailed its effect on the migratory function of cardiac fibroblasts (CFs) in response to TGF-β1.
  
  
  RESULTS
  In healthy murine myocardium, fibulin-6 expression is largely confined to larger coronary arteries. It is induced during the early and the late phase of remodelling after infarction in murine hearts predominantly in the scar-muscle junction. Similar results are obtained in human ischaemic cardiomyopathy. Fibulin-6 is mostly expressed in close vicinity to vimentin-positive cells and is also abundantly expressed in vitro in cultured neonatal CF. TGF-β1 does not induce smooth muscle actin in fibroblasts deficient of fibulin-6, which also compromised their migration. Cells that had migrated expressed more fibulin-6 compared with stationary cells. Plated on fibulin-6-depleted matrix, stress fibre induction in fibroblast in response to TGF-β1 was impaired. In ex vivo explant cultures from post-infarct myocardium, the number of emigrating fibroblasts was also significantly reduced by fibulin-6 siRNA knockdown.
  
  
  CONCLUSIONS
  Fibulin-6, a fibroblast-released ECM protein, may play an important role during MR by imparting an effect on CF migration in close and complementary interplay with TGF-β1 signalling.
authors.affiliation: Department of Anesthesiology and Intensive Care Medicine, Hannover Medical School, Carl-Neuberg Str. 1, 30625 Hannover, Germany.
authors.forename: Arpita
authors.initials: A
authors.lastname: Chowdhury
authors.affiliation: Department of Anesthesiology and Intensive Care Medicine, Hannover Medical School, Carl-Neuberg Str. 1, 30625 Hannover, Germany.
authors.forename: Christine
authors.initials: C
authors.lastname: Herzog
authors.affiliation: Department of Anesthesiology and Intensive Care Medicine, Hannover Medical School, Carl-Neuberg Str. 1, 30625 Hannover, Germany.
authors.forename: Lisa
authors.initials: L
authors.lastname: Hasselbach
authors.affiliation: Department of Anesthesiology and Intensive Care Medicine, Hannover Medical School, Carl-Neuberg Str. 1, 30625 Hannover, Germany.
authors.forename: Houra Loghmani
authors.initials: HL
authors.lastname: Khouzani
authors.affiliation: Institute of Developmental Biology, Cologne University, Cologne, Germany.
authors.forename: Jinli
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Institute of Developmental Biology, Cologne University, Cologne, Germany.
authors.forename: Matthias
authors.initials: M
authors.lastname: Hammerschmidt
authors.affiliation: Institute for Molecular Biology, Hannover Medical School, Hannover, Germany.
authors.forename: Carsten
authors.initials: C
authors.lastname: Rudat
authors.affiliation: Institute for Molecular Biology, Hannover Medical School, Hannover, Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: Kispert
authors.affiliation: Institute of Physiological Chemistry, Hannover Medical School, Hannover, Germany.
authors.forename: Matthias
authors.initials: M
authors.lastname: Gaestel
authors.affiliation: Institute of Physiological Chemistry, Hannover Medical School, Hannover, Germany.
authors.forename: Manoj B
authors.initials: MB
authors.lastname: Menon
authors.affiliation: Department of Cardio-Thoracic, Transplantation and Vascular Surgery, Hannover Medical School, Hannover, Germany.
authors.forename: Igor
authors.initials: I
authors.lastname: Tudorache
authors.affiliation: Department of Cardiology and Angiology, Hannover Medical School, Hannover, Germany.
authors.forename: Denise
authors.initials: D
authors.lastname: Hilfiker-Kleiner
authors.affiliation: Institute of Applied Anatomy, Hannover Medical School, Hannover, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Mühlfeld
authors.affiliation: Department of Cardio-Thoracic, Transplantation and Vascular Surgery, Hannover Medical School, Hannover, Germany.
authors.forename: Jan Dieter
authors.initials: JD
authors.lastname: Schmitto
authors.affiliation: Department of Anesthesiology and Intensive Care Medicine, Hannover Medical School, Carl-Neuberg Str. 1, 30625 Hannover, Germany.
authors.forename: Martin
authors.initials: M
authors.lastname: Müller
authors.affiliation: Department of Anesthesiology and Intensive Care Medicine, Hannover Medical School, Carl-Neuberg Str. 1, 30625 Hannover, Germany theilmeier.gregor@mh-hannover.de.
authors.forename: Gregor
authors.initials: G
authors.lastname: Theilmeier
mesh_terms: D000818:Animals; D002465:Cell Movement / Q000502:physiology*; D016326:Extracellular Matrix Proteins / Q000378:metabolism*; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism*; D006801:Humans; D007136:Immunoglobulins / Q000378:metabolism*; D008810:Mice, Inbred C57BL; D009203:Myocardial Infarction; D009206:Myocardium / Q000166:cytology / Q000378:metabolism*; D053773:Transforming Growth Factor beta1 / Q000378:metabolism
chemical_list: D016326:Extracellular Matrix Proteins; C488168:HMCN1 protein, human; D007136:Immunoglobulins; D053773:Transforming Growth Factor beta1; C517185:hemicentin 1 protein, mouse
keywords: Fibroblast; Fibulin-6; Migration; Myocardial ischaemia; Myocardial remodelling