Dilated cardiomyopathy in transgenic mice expressing a dominant-negative CREB transcription factor in the heart
Dilated cardiomyopathy in transgenic mice expressing a dominant-negative CREB transcription factor in the heart
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DOI：
10.1172/jci2950
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发表时间：
1998-06-01
影响因子：
15.9
通讯作者：
Leiden, JM
中科院分区：
文献类型：
--
作者：
Fentzke, RC;Korcarz, CE;Leiden, JM
特发性扩张型心肌病（IDC）是一种常见的原发性心肌疾病，其病因不明，以进行性双心室衰竭、心脏扩张和过早死亡为特征。在这里，我们表明，转基因小鼠表达的CREB转录因子显性阴性形式，在心肌细胞特异性α-MHC启动子的控制下，这些小鼠（CREBA 133）发展扩张型心肌病，其非常类似于人IDC的许多解剖学、生理学和临床特征。在2至20周龄之间，这些小鼠发展四腔心脏扩张，左心室收缩和舒张功能降低，对β-肾上腺素能激动剂异丙肾上腺素的收缩反应减弱。组织学上，CREBA 133心脏表现出萎缩和肥大的纤维以及显著的间质纤维化。这些解剖学和血流动力学变化与肝充血和外周水肿、心内血栓和过早死亡相关。两者合计，这些结果暗示CREB作为一个重要的调节心肌细胞功能，并提供了一个遗传模型扩张型心肌病，这将有助于研究的发病机制和治疗这一临床上重要的疾病。
Idiopathic-dilated cardiomyopathy (IDC) is a common primary myocardial disease of unknown etiology characterized by progressive biventricular failure, cardiac dilatation, and premature mortality. Here we show that transgenic mice expressing a dominant-negative form of the CREB transcription factor (CREBA133) under the control of the cardiac myocyte-specific alpha-MHC promoter develop dilated cardiomyopathy that closely resembles many of the anatomical, physiological, and clinical features of human IDC, Between 2 and 20 wk of age, these mice develop four chamber cardiac dilatation, decreased systolic and diastolic left ventricular function, and attenuated contractile responses to the beta-adrenergic agonist, isoproterenol. Histologically, the CREBA133 hearts demonstrated both atrophic and hypertrophied fibers as well as significant interstitial fibrosis, These anatomical and hemodynamic changes were associated with hepatic congestion and peripheral edema, intracardiac thrombi, and premature mortality. Taken together, these results implicate CREB as an important regulator of cardiac myocyte function and provide a genetic model of dilated cardiomyopathy which should facilitate studies of both the pathogenesis and therapy of this clinically important disorder.