Osteopontin (OPN) is not expressed in healthy heart while, its expression is dramatically increased in cardiomyocytes and inﬂammatory cells during cardiomyopathies and heart failure. However its role in the development of heart diseases is not known.
To understand whether OPN is involved in cardiomyopathy, we created a transgenic mouse (MHC-OPN) expressing recombinant OPN (rOPN) speciﬁcally in cardiomyocytes using aMHC promoter-directed OPN expression and tTA technology. In these mice, rOPN expression could be regulated by doxycyclin oral administration.
After birth, MHC-OPN young mice were phenotypically indistinguishable from their littermate controls, but most of them died early between the 8 th and 15 th weeks after birth with a half life of 12 weeks. However, less than 10 % MHC-OPN mice survived and were still alive 30 weeks after birth. Inhibition of recombinant OPN expression by doxycyclin at the beginning of T cell inﬁltration (5 weeks after birth) or when DCM was initiated (11 weeks after birth) reduced myocarditis and thus avoided the early death.
Electrocardiography demonstrated atrio-ventricular and intra ventricular defects. Moreover, echocardiography showed left ventricular dilation without hypertrophy and a systolic dysfunction, as indicated by reduced left ventricular fractional shortening (control mice: 29,8±2,0 %, n=13 ; and MHC-OPN mice: 13,7±4,0 %, n=5 ; T test p<0.05). In vitro histology conﬁrmed that mice died because of a dilated cardiomyopathy associated with a strong ﬁbrosis.
By immunohistology, we demonstrated that OPN expression in cardiomyocytes induced an important cell inﬁltration including some macrophages and a large number of ﬁbroblasts and activated CD4+ and CD8+ T cells.
All together these experiments suggested that chronic OPN expression is required for DCM development inducing Tcell activation and thus a chronic myocarditis resulting in the dilated cardiomyopathy.Le texte complet de cet article est disponible en PDF.
Keywords : Dilated cardiomyopathy, myocarditis, osteopontin, transgenic mouse