title: Breeding Strategy Determines Rupture Incidence in Post-Infarct Healing WARPing Cardiovascular Research.
abstract: BACKGROUND
  Von Willebrand A domain Related Protein (WARP), is a recently identified extracellular matrix protein. Based upon its involvement in matrix biology and its expression in the heart, we hypothesized that WARP regulates cardiac remodeling processes in the post-infarct healing process.
  
  
  RESULTS
  In the mouse model of myocardial infarction (MI), WARP expression increased in the infarcted area 3-days post-MI. In the healthy myocardium WARP localized with perlecan in the basement membrane, which was disrupted upon injury. In vitro studies showed high expression of WARP by cardiac fibroblasts, which further increases upon TGFβ stimulation. Furthermore, WARP expression correlated with aSMA and COL1 expression, markers of fibroblast to myofibroblast transition, in vivo and in vitro. Finally, WARP knockdown in vitro affected extra- and intracellular basic fibroblast growth factor production in myofibroblasts. To investigate the function for WARP in infarction healing, we performed an MI study in WARP knockout (KO) mice backcrossed more than 10 times on an Australian C57Bl/6-J background and bred in-house, and compared to wild type (WT) mice of the same C57Bl/6-J strain but of commercial European origin. WARP KO mice showed no mortality after MI, whereas 40% of the WT mice died due to cardiac rupture. However, when WARP KO mice were backcrossed on the European C57Bl/6-J background and bred heterozygous in-house, the previously seen protective effect in the WARP KO mice after MI was lost. Importantly, comparison of the cardiac response post-MI in WT mice bred heterozygous in-house versus commercially purchased WT mice revealed differences in cardiac rupture.
  
  
  CONCLUSIONS
  These data demonstrate a redundant role for WARP in the wound healing process after MI but demonstrate that the continental/breeding/housing origin of mice of the same C57Bl6-J strain is critical in determining the susceptibility to cardiac rupture and stress the importance of using the correct littermate controls.
authors.affiliation: Department of Cardiology, Maastricht University, Maastricht, The Netherlands; Centre for Molecular and Vascular Biology, KULeuven, Leuven, Belgium.
authors.forename: Sophie
authors.initials: S
authors.lastname: Deckx
authors.affiliation: Department of Cardiology, Maastricht University, Maastricht, The Netherlands; Centre for Molecular and Vascular Biology, KULeuven, Leuven, Belgium.
authors.forename: Paolo
authors.initials: P
authors.lastname: Carai
authors.affiliation: Murdoch Children's Research Institute, University of Melbourne, Royal Children's Hospital, Parkville, Victoria, Australia; Department of Paediatrics, University of Melbourne, Royal Children's Hospital, Parkville, Victoria, Australia.
authors.forename: John
authors.initials: J
authors.lastname: Bateman
authors.affiliation: Department of Cardiology, Maastricht University, Maastricht, The Netherlands; Centre for Molecular and Vascular Biology, KULeuven, Leuven, Belgium.
authors.forename: Stephane
authors.initials: S
authors.lastname: Heymans
authors.affiliation: Department of Cardiology, Maastricht University, Maastricht, The Netherlands; Centre for Molecular and Vascular Biology, KULeuven, Leuven, Belgium.
authors.forename: Anna-Pia
authors.initials: AP
authors.lastname: Papageorgiou
mesh_terms: D000199:Actins / Q000235:genetics / Q000378:metabolism; D000818:Animals; D002454:Cell Differentiation; D002478:Cells, Cultured; D024042:Collagen Type I / Q000235:genetics / Q000378:metabolism; D016326:Extracellular Matrix Proteins / Q000235:genetics / Q000378:metabolism*; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism; D006341:Heart Rupture / Q000209:etiology / Q000235:genetics*; D007178:Inbreeding; D051379:Mice; D008810:Mice, Inbred C57BL; D009203:Myocardial Infarction / Q000150:complications / Q000235:genetics*; D032383:Myocytes, Cardiac / Q000166:cytology / Q000378:metabolism; D051381:Rats; D012038:Regeneration / Q000235:genetics
chemical_list: D000199:Actins; D024042:Collagen Type I; D016326:Extracellular Matrix Proteins; C460761:WARP protein, mouse; C544013:alpha-smooth muscle actin, mouse