title: Deficiency of filamin A in endothelial cells impairs left ventricular remodelling after myocardial infarction.
abstract: OBJECTIVE
  Actin-binding protein filamin A (FLNA) regulates signal transduction important for cell locomotion, but the role of FLNA after myocardial infarction (MI) has not been explored. The main purpose of this study was to determine the impact of endothelial deletion of FLNA on post-MI remodelling of the left ventricle (LV).
  
  
  RESULTS
  We found that FLNA is expressed in human and mouse endothelial cells (ECs) during MI. To determine the biological significance of endothelial expression of FLNA, we used mice that are deficient for endothelial FLNA by cross-breeding adult mice expressing floxed Flna (Flna(o/fl)) with mice expressing Cre under the vascular endothelial-specific cadherin promoter (VECadCre+). Male Flna(o/fl) and Flna(o/fl)/VECadCre+ mice were subjected to permanent coronary artery ligation to induce MI. Flna(o/fl)/VECadCre+ mice that were deficient for endothelial FLNA exhibited larger and thinner LV with impaired cardiac function as well as elevated plasma levels of NT-proBNP and decreased secretion of VEGF-A. The number of capillary structures within the infarcted areas was reduced in Flna(o/fl)/VECadCre+ hearts. ECs silenced for Flna mRNA expression exhibited impaired tubular formation and migration, secreted less VEGF-A, and produced lower levels of phosphorylated AKT and ERK1/2 as well as active RAC1.
  
  
  CONCLUSIONS
  Deletion of FLNA in ECs aggravated MI-induced LV dysfunction and cardiac failure as a result of defective endothelial response and increased scar formation by impaired endothelial function and signalling.
authors.affiliation: Department of Medical Biochemistry and Cell Biology, Institute of Biomedicine, University of Gothenburg, Medicinaregatan 9A, SE-405 30 Gothenburg, Sweden.
authors.forename: Sashidar
authors.initials: S
authors.lastname: Bandaru
authors.affiliation: AstraZeneca, Mölndal, Sweden.
authors.forename: Julia
authors.initials: J
authors.lastname: Grönros
authors.affiliation: Cardiovascular and Metabolic Research Center, University of Gothenburg, Gothenburg, Sweden Department of Cardiology, Sahlgrenska Academy Hospital, Gothenburg, Sweden.
authors.forename: Björn
authors.initials: B
authors.lastname: Redfors
authors.affiliation: Department of Medical Biochemistry and Cell Biology, Institute of Biomedicine, University of Gothenburg, Medicinaregatan 9A, SE-405 30 Gothenburg, Sweden.
authors.forename: Çağlar
authors.initials: Ç
authors.lastname: Çil
authors.affiliation: Department of Surgery, Sahlgrenska Academy Hospital, Gothenburg, Sweden.
authors.forename: David
authors.initials: D
authors.lastname: Pazooki
authors.affiliation: Department of Medical Biochemistry and Cell Biology, Institute of Biomedicine, University of Gothenburg, Medicinaregatan 9A, SE-405 30 Gothenburg, Sweden.
authors.forename: Reza
authors.initials: R
authors.lastname: Salimi
authors.affiliation: Department of Medical Biochemistry and Cell Biology, Institute of Biomedicine, University of Gothenburg, Medicinaregatan 9A, SE-405 30 Gothenburg, Sweden.
authors.forename: Erik
authors.initials: E
authors.lastname: Larsson
authors.affiliation: Cardiovascular and Metabolic Research Center, University of Gothenburg, Gothenburg, Sweden.
authors.forename: Alex-Xianghua
authors.initials: AX
authors.lastname: Zhou
authors.affiliation: Cardiovascular and Metabolic Research Center, University of Gothenburg, Gothenburg, Sweden Department of Cardiology, Sahlgrenska Academy Hospital, Gothenburg, Sweden.
authors.forename: Elmir
authors.initials: E
authors.lastname: Ömerovic
authors.affiliation: Department of Medical Biochemistry and Cell Biology, Institute of Biomedicine, University of Gothenburg, Medicinaregatan 9A, SE-405 30 Gothenburg, Sweden Department of Clinical Pathology and Genetics, Sahlgrenska Academy Hospital, Gothenburg, Sweden levent.akyurek@gu.se.
authors.forename: Levent M
authors.initials: LM
authors.lastname: Akyürek
mesh_terms: D000818:Animals; D042783:Endothelial Cells / Q000378:metabolism*; D064448:Filamins / Q000172:deficiency / Q000378:metabolism*; D006333:Heart Failure / Q000235:genetics; D006352:Heart Ventricles / Q000503:physiopathology*; D008297:Male; D008822:Mice, Transgenic; D009203:Myocardial Infarction / Q000235:genetics / Q000378:metabolism*; D018487:Ventricular Dysfunction, Left / Q000235:genetics*; D020257:Ventricular Remodeling / Q000235:genetics*
chemical_list: D064448:Filamins; C529499:FlnA protein, mouse
keywords: Actin-binding protein; Angiogenesis; Cell migration; Heart