Absence of thrombospondin-2 causes age-related dilated cardiomyopathy.
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.
Swinnen
Melissa
M
Center for Heart Failure Research, CARIM, Maastricht University, Maastricht, the Netherlands.
Vanhoutte
Davy
D
Van Almen
Geert C
GC
Hamdani
Nazha
N
Schellings
Mark W M
MW
D'hooge
Jan
J
Van der Velden
Jolanda
J
Weaver
Matthew S
MS
Sage
E Helene
EH
Bornstein
Paul
P
Verheyen
Fons K
FK
VandenDriessche
Thierry
T
Chuah
Marinee K
MK
Westermann
Dirk
D
Paulus
Walter J
WJ
Van de Werf
Frans
F
Schroen
Blanche
B
Carmeliet
Peter
P
Pinto
Yigal M
YM
Heymans
Stephane
S
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
D020778:Matrix Metalloproteinase 2; D051057:Proto-Oncogene Proteins c-akt; D019699:Thrombospondins; D000099262:Thrombospondin 2