title: Protection against myocardial infarction and no-reflow through preservation of vascular integrity by angiopoietin-like 4.
abstract: BACKGROUND
  Increased permeability, predominantly controlled by endothelial junction stability, is an early event in the deterioration of vascular integrity in ischemic disorders. Hemorrhage, edema, and inflammation are the main features of reperfusion injuries, as observed in acute myocardial infarction (AMI). Thus, preservation of vascular integrity is fundamental in ischemic heart disease. Angiopoietins are pivotal modulators of cell-cell junctions and vascular integrity. We hypothesized that hypoxic induction of angiopoietin-like protein 4 (ANGPTL4) might modulate vascular damage, infarct size, and no-reflow during AMI.
  
  
  RESULTS
  We showed that vascular permeability, hemorrhage, edema, inflammation, and infarct severity were increased in angptl4-deficient mice. We determined that decrease in vascular endothelial growth factor receptor 2 (VEGFR2) and VE-cadherin expression and increase in Src kinase phosphorylation downstream of VEGFR2 were accentuated after ischemia-reperfusion in the coronary microcirculation of angptl4-deficient mice. Both events led to altered VEGFR2/VE-cadherin complexes and to disrupted adherens junctions in the endothelial cells of angptl4-deficient mice that correlated with increased no-reflow. In vivo injection of recombinant human ANGPTL4 protected VEGF-driven dissociation of the VEGFR2/VE-cadherin complex, reduced myocardial infarct size, and the extent of no-reflow in mice and rabbits.
  
  
  CONCLUSIONS
  These data showed that ANGPTL4 might constitute a relevant target for therapeutic vasculoprotection aimed at counteracting the effects of VEGF, thus being crucial for preventing no-reflow and conferring secondary cardioprotection during AMI.
authors.affiliation: Collège de France, Center for Interdisciplinary Research in Biology, 11 Place Marcelin Berthelot, Paris, F-75005, France.
authors.forename: Ariane
authors.initials: A
authors.lastname: Galaup
authors.forename: Elisa
authors.initials: E
authors.lastname: Gomez
authors.forename: Rachid
authors.initials: R
authors.lastname: Souktani
authors.forename: Mélanie
authors.initials: M
authors.lastname: Durand
authors.forename: Aurélie
authors.initials: A
authors.lastname: Cazes
authors.forename: Catherine
authors.initials: C
authors.lastname: Monnot
authors.forename: Jérémie
authors.initials: J
authors.lastname: Teillon
authors.forename: Sébastien
authors.initials: S
authors.lastname: Le Jan
authors.forename: Claire
authors.initials: C
authors.lastname: Bouleti
authors.forename: Gaëlle
authors.initials: G
authors.lastname: Briois
authors.forename: Josette
authors.initials: J
authors.lastname: Philippe
authors.forename: Sandrine
authors.initials: S
authors.lastname: Pons
authors.forename: Valérie
authors.initials: V
authors.lastname: Martin
authors.forename: Rana
authors.initials: R
authors.lastname: Assaly
authors.forename: Philippe
authors.initials: P
authors.lastname: Bonnin
authors.forename: Philippe
authors.initials: P
authors.lastname: Ratajczak
authors.forename: Anne
authors.initials: A
authors.lastname: Janin
authors.forename: Gavin
authors.initials: G
authors.lastname: Thurston
authors.forename: David M
authors.initials: DM
authors.lastname: Valenzuela
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Murphy
authors.forename: George D
authors.initials: GD
authors.lastname: Yancopoulos
authors.forename: Renaud
authors.initials: R
authors.lastname: Tissier
authors.forename: Alain
authors.initials: A
authors.lastname: Berdeaux
authors.forename: Bijan
authors.initials: B
authors.lastname: Ghaleh
authors.forename: Stéphane
authors.initials: S
authors.lastname: Germain
mesh_terms: D000075803:Angiopoietin-Like Protein 4; D042682:Angiopoietins / Q000172:deficiency / Q000627:therapeutic use*; D000818:Animals; D002316:Cardiotonic Agents / Q000378:metabolism / Q000627:therapeutic use; D002478:Cells, Cultured; D004730:Endothelium, Vascular / Q000166:cytology / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009203:Myocardial Infarction / Q000378:metabolism* / Q000473:pathology / Q000517:prevention & control*; D032383:Myocytes, Cardiac / Q000378:metabolism; D054318:No-Reflow Phenomenon / Q000378:metabolism* / Q000517:prevention & control*; D011817:Rabbits; D011897:Random Allocation
chemical_list: D000075803:Angiopoietin-Like Protein 4; D042682:Angiopoietins; C407088:Angptl4 protein, mouse; D002316:Cardiotonic Agents