INSERM U828, Ave. du Haut Lévêque, Pessac, France.
Circ Heart Fail. 2010 May;3(3):431-9. doi: 10.1161/CIRCHEARTFAILURE.109.898114. Epub 2010 Mar 3.
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.
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.
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.
炎症过程在心肌炎、扩张型心肌病和心力衰竭中起着关键作用。在人类和动物的心肌炎和心力衰竭中，炎症趋化因子骨桥蛋白 (OPN) 在心肌细胞和炎症细胞中的表达显著增加。然而，其在心脏病发展中的作用尚不清楚。
为了了解 OPN 是否参与心肌病的发生，我们构建了一种转基因小鼠（MHC-OPN），该小鼠在心肌细胞中特异性过表达 OPN，其表达受心脏特异性启动子调控。年轻的 MHC-OPN 小鼠在表型上与对照同窝仔鼠没有区别，但它们中的大多数在 12 周龄时过早死亡，半衰期为 12 周。心电图显示传导缺陷。超声心动图显示左心室扩张和收缩功能障碍。组织学分析显示心肌细胞丢失、严重纤维化和炎症细胞浸润。这些炎症细胞大多数是具有 Th1 极化和细胞毒性活性的活化 T 细胞。在 MHC-OPN 小鼠的血清中未发现针对 OPN、心肌肌球蛋白或肌钙蛋白 I 的自身抗体。
这些数据表明，心脏中 OPN 的表达会导致体内 T 细胞募集和激活，从而引发慢性心肌炎，其结果是心肌细胞破坏，进而导致扩张型心肌病。因此，OPN 可能成为限制心力衰竭的潜在治疗靶点。
