title: Absence of SPARC results in increased cardiac rupture and dysfunction after acute myocardial infarction.
abstract: The matricellular protein SPARC (secreted protein, acidic and rich in cysteine, also known as osteonectin) mediates cell-matrix interactions during wound healing and regulates the production and/or assembly of the extracellular matrix (ECM). This study investigated whether SPARC functions in infarct healing and ECM maturation after myocardial infarction (MI). In comparison with wild-type (WT) mice, animals with a targeted inactivation of SPARC exhibited a fourfold increase in mortality that resulted from an increased incidence of cardiac rupture and failure after MI. SPARC-null infarcts had a disorganized granulation tissue and immature collagenous ECM. In contrast, adenoviral overexpression of SPARC in WT mice improved the collagen maturation and prevented cardiac dilatation and dysfunction after MI. In cardiac fibroblasts in vitro, reduction of SPARC by short hairpin RNA attenuated transforming growth factor beta (TGF)-mediated increase of Smad2 phosphorylation, whereas addition of recombinant SPARC increased Smad2 phosphorylation concordant with increased Smad2 phosphorylation in SPARC-treated mice. Importantly, infusion of TGF-beta rescued cardiac rupture in SPARC-null mice but did not significantly alter infarct healing in WT mice. These findings indicate that local production of SPARC is essential for maintenance of the integrity of cardiac ECM after MI. The protective effects of SPARC emphasize the potential therapeutic applications of this protein to prevent cardiac dilatation and dysfunction after MI.
authors.affiliation: Center for Heart Failure Research, Cardiovascular Research Institute Maastricht, University Hospital Maastricht, 6229 HX Maastricht, The Netherlands.
authors.forename: Mark W M
authors.initials: MW
authors.lastname: Schellings
authors.forename: Davy
authors.initials: D
authors.lastname: Vanhoutte
authors.forename: Melissa
authors.initials: M
authors.lastname: Swinnen
authors.forename: Jack P
authors.initials: JP
authors.lastname: Cleutjens
authors.forename: Jacques
authors.initials: J
authors.lastname: Debets
authors.forename: Rick E W
authors.initials: RE
authors.lastname: van Leeuwen
authors.forename: Jan
authors.initials: J
authors.lastname: d'Hooge
authors.forename: Frans
authors.initials: F
authors.lastname: Van de Werf
authors.forename: Peter
authors.initials: P
authors.lastname: Carmeliet
authors.forename: Yigal M
authors.initials: YM
authors.lastname: Pinto
authors.forename: E Helene
authors.initials: EH
authors.lastname: Sage
authors.forename: Stephane
authors.initials: S
authors.lastname: Heymans
mesh_terms: D000818:Animals; D002135:Calcium-Binding Proteins / Q000235:genetics; D016326:Extracellular Matrix Proteins / Q000235:genetics; D005260:Female; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism; D006097:Granulation Tissue / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D006321:Heart / Q000503:physiopathology; D006342:Heart Rupture, Post-Infarction / Q000378:metabolism* / Q000503:physiopathology / Q000517:prevention & control; D006439:Hemodynamics / Q000502:physiology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009203:Myocardial Infarction / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D015676:Osteonectin / Q000172:deficiency* / Q000235:genetics / Q000502:physiology; D051381:Rats; D011917:Rats, Inbred Lew; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects; D051899:Smad2 Protein / Q000235:genetics; D016019:Survival Analysis; D016212:Transforming Growth Factor beta / Q000494:pharmacology / Q000502:physiology / Q000627:therapeutic use
chemical_list: D002135:Calcium-Binding Proteins; D016326:Extracellular Matrix Proteins; D015676:Osteonectin; C524549:SMOC-1 protein, mouse; C513851:SMOC-2 protein, mouse; D051899:Smad2 Protein; C497783:Smad2 protein, mouse; C503127:Sparcl1 protein, mouse; D016212:Transforming Growth Factor beta