Osteopontin expression in cardiomyocytes induces dilated cardiomyopathy.
BACKGROUND
Inflammatory processes play a critical role in myocarditis, dilated cardiomyopathy, and heart failure. The expression of the inflammatory chemokine osteopontin (OPN) is dramatically increased in cardiomyocytes and inflammatory cells during myocarditis and heart failure in human and animals. However, its role in the development of heart diseases is not known.


RESULTS
To understand whether OPN is involved in cardiomyopathies, we generated a transgenic mouse (MHC-OPN) that specifically overexpresses OPN in cardiomyocytes with cardiac-specific promoter-directed OPN expression. Young MHC-OPN mice were phenotypically indistinguishable from their control littermates, but most of them died prematurely with a half-life of 12 weeks of age. Electrocardiography revealed conduction defects. Echocardiography showed left ventricular dilation and systolic dysfunction. Histological analysis revealed cardiomyocyte loss, severe fibrosis, and inflammatory cell infiltration. Most of these inflammatory cells were activated T cells with Th1 polarization and cytotoxic activity. Autoantibodies against OPN, cardiac myosin, or troponin I, were not found in the serum of MHC-OPN mice.


CONCLUSIONS
These data show that OPN expression in the heart induces in vivo T-cell recruitment and activation leading to chronic myocarditis, the consequence of which is myocyte destruction and hence, dilated cardiomyopathy. Thus, OPN might therefore constitute a potential therapeutic target to limit heart failure.
Renault
Marie-Ange
MA
INSERM U828, Ave. du Haut Lévêque, Pessac, France.
Robbesyn
Fanny
F
Réant
Patricia
P
Douin
Victorine
V
Daret
Danièle
D
Allières
Cécile
C
Belloc
Isabelle
I
Couffinhal
Thierry
T
Arnal
Jean-François
JF
Klingel
Karin
K
Desgranges
Claude
C
Dos Santos
Pierre
P
Charpentier
Flavien
F
Gadeau
Alain-Pierre
AP
D000818:Animals; D002311:Cardiomyopathy, Dilated / Q000209:etiology / Q000378:metabolism* / Q000473:pathology*; D004195:Disease Models, Animal; D005355:Fibrosis / Q000209:etiology / Q000378:metabolism / Q000473:pathology; D006333:Heart Failure / Q000209:etiology / Q000378:metabolism* / Q000473:pathology*; D008213:Lymphocyte Activation; D051379:Mice; D008822:Mice, Transgenic; D009205:Myocarditis / Q000209:etiology / Q000378:metabolism / Q000473:pathology; D032383:Myocytes, Cardiac / Q000378:metabolism*; D020556:Neutrophil Infiltration; D053495:Osteopontin / Q000378:metabolism*
D053495:Osteopontin