Cardiac compartment-specific overexpression of a modified retinoic acid receptor produces dilated cardiomyopathy and congestive heart failure in transgenic mice
Cardiac compartment-specific overexpression of a modified retinoic acid receptor produces dilated cardiomyopathy and congestive heart failure in transgenic mice
复制标题
DOI：
10.1172/jci119727
复制
发表时间：
1997-10-15
影响因子：
15.9
通讯作者：
Robbins, J
中科院分区：
文献类型：
--
作者：
Colbert, MC;Hall, DG;Robbins, J
类维生素A在心脏形态发生中起关键作用。为了检查过量的类维生素A信号传导对心肌发育的影响，产生了过表达由α-或β-肌球蛋白重链（MyHC）启动子控制的组成型活性视黄酸受体（RAR）的转基因小鼠。携带α-MyHC-RAR转基因的动物在胚胎心房和成年心房和心室中表达RAR，但没有出现畸形或疾病的迹象。相比之下，β-MyHC-RAR动物，其中表达在胎儿心室中被激活，发展为扩张型心肌病，其严重程度随转基因拷贝数而变化。特征性死后病变包括双心室腔扩张和左心房血栓形成;这些病变的发生率和严重程度随着拷贝数的增加而增加。转录分析显示肥大的分子标志物，α-骨骼肌动蛋白，心房利钠因子和β-MyHC，上调。采用离体灌流工作心脏模型，经胸M型超声心动图评价转基因心脏的心脏性能。两项分析均显示左心室功能中度至重度受损和心肌收缩力降低。因此，组成型活性RAR在发育中的心房和/或出生后的心室中的表达是相对良性的，而妊娠期间的心室表达可导致显著的心功能障碍。
Retinoids play a critical role in cardiac morphogenesis. To examine the effects of excessive retinoid signaling on myocardial development, transgenic mice that overexpress a constitutively active retinoic acid receptor (RAR) controlled by either the alpha- or beta-myosin heavy chain (MyHC) promoter were generated. Animals carrying the alpha-MyHC-RAR transgene expressed RARs in embryonic atria and in adult atria and ventricles, but developed no signs of either malformations or disease. In contrast, beta-MyHC-RAR animals, where expression was activated in fetal ventricles, developed a dilated cardiomyopathy that varied in severity with transgene copy number. Characteristic postmortem lesions included biventicular chamber dilation and left atrial thrombosis; the incidence and severity of these lesions increased with increasing copy number. Transcript analyses showed that molecular markers of hypertrophy, alpha-skeletal actin, atrial natriuretic factor and beta-MyHC, were upregulated. Cardiac performance of transgenic hearts was evaluated using the isolated perfused working heart model as web as in vivo, by transthoracic M-mode echocardiography. Both analyses showed moderate to severe impairment of left ventricular function and reduced cardiac contractility. Thus, expression of a constitutively active RAR in developing atria and/or in postnatal ventricles is relatively benign, while ventricular expression during gestation can lead to significant cardiac dysfunction.