title: Absence of thrombospondin-2 causes age-related dilated cardiomyopathy.
abstract: BACKGROUND
  The progressive shift from a young to an aged heart is characterized by alterations in the cardiac matrix. The present study investigated whether the matricellular protein thrombospondin-2 (TSP-2) may affect cardiac dimensions and function with physiological aging of the heart.
  
  
  RESULTS
  TSP-2 knockout (KO) and wild-type mice were followed up to an age of 60 weeks. Survival rate, cardiac function, and morphology did not differ at a young age in TSP-2 KO compared with wild-type mice. However, >55% of the TSP-2 KO mice died between 24 and 60 weeks of age, whereas <10% of the wild-type mice died. In the absence of TSP-2, older mice displayed a severe dilated cardiomyopathy with impaired systolic function, increased cardiac dilatation, and fibrosis. Ultrastructural analysis revealed progressive myocyte stress and death, accompanied by an inflammatory response and replacement fibrosis, in aging TSP-2 KO animals, whereas capillary or coronary morphology or density was not affected. Importantly, adeno-associated virus-9 gene-mediated transfer of TSP-2 in 7-week-old TSP-2 KO mice normalized their survival and prevented dilated cardiomyopathy. In TSP-2 KO animals, age-related cardiomyopathy was accompanied by increased matrix metalloproteinase-2 and decreased tissue transglutaminase-2 activity, together with impaired collagen cross-linking. At the cardiomyocyte level, TSP-2 deficiency in vivo and its knockdown in vitro decreased the activation of the Akt survival pathway in cardiomyocytes.
  
  
  CONCLUSIONS
  TSP-2 expression in the heart protects against age-dependent dilated cardiomyopathy.
authors.affiliation: Center for Heart Failure Research, CARIM, Maastricht University, Maastricht, the Netherlands.
authors.forename: Melissa
authors.initials: M
authors.lastname: Swinnen
authors.forename: Davy
authors.initials: D
authors.lastname: Vanhoutte
authors.forename: Geert C
authors.initials: GC
authors.lastname: Van Almen
authors.forename: Nazha
authors.initials: N
authors.lastname: Hamdani
authors.forename: Mark W M
authors.initials: MW
authors.lastname: Schellings
authors.forename: Jan
authors.initials: J
authors.lastname: D'hooge
authors.forename: Jolanda
authors.initials: J
authors.lastname: Van der Velden
authors.forename: Matthew S
authors.initials: MS
authors.lastname: Weaver
authors.forename: E Helene
authors.initials: EH
authors.lastname: Sage
authors.forename: Paul
authors.initials: P
authors.lastname: Bornstein
authors.forename: Fons K
authors.initials: FK
authors.lastname: Verheyen
authors.forename: Thierry
authors.initials: T
authors.lastname: VandenDriessche
authors.forename: Marinee K
authors.initials: MK
authors.lastname: Chuah
authors.forename: Dirk
authors.initials: D
authors.lastname: Westermann
authors.forename: Walter J
authors.initials: WJ
authors.lastname: Paulus
authors.forename: Frans
authors.initials: F
authors.lastname: Van de Werf
authors.forename: Blanche
authors.initials: B
authors.lastname: Schroen
authors.forename: Peter
authors.initials: P
authors.lastname: Carmeliet
authors.forename: Yigal M
authors.initials: YM
authors.lastname: Pinto
authors.forename: Stephane
authors.initials: S
authors.lastname: Heymans
mesh_terms: D000375:Aging; D000818:Animals; D002311:Cardiomyopathy, Dilated / Q000209:etiology* / Q000401:mortality / Q000473:pathology / Q000517:prevention & control; D016923:Cell Death; D004789:Enzyme Activation; D005260:Female; D005355:Fibrosis; D018014:Gene Transfer Techniques; D008297:Male; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D009205:Myocarditis / Q000209:etiology; D009206:Myocardium / Q000378:metabolism* / Q000473:pathology; D032383:Myocytes, Cardiac / Q000378:metabolism / Q000648:ultrastructure; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D019699:Thrombospondins / Q000172:deficiency* / Q000235:genetics; D015854:Up-Regulation; D000099262:Thrombospondin 2
chemical_list: D020778:Matrix Metalloproteinase 2; D051057:Proto-Oncogene Proteins c-akt; D019699:Thrombospondins; D000099262:Thrombospondin 2