Cardiac-specific overexpression of RhoA results in sinus and atrioventricular nodal dysfunction and contractile failure
Cardiac-specific overexpression of RhoA results in sinus and atrioventricular nodal dysfunction and contractile failure
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DOI：
10.1172/jci6842
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发表时间：
1999-06-01
影响因子：
15.9
通讯作者：
Brown, JH
中科院分区：
文献类型：
--
作者：
Sah, VP;Minamisawa, S;Brown, JH
RhoA是一种低分子量的谷胱甘肽，参与调节肥大心肌细胞的生长。为了研究RhoA在体内控制心脏功能中的作用，产生了在心脏特异性α-肌球蛋白重链启动子的控制下表达RhoA的野生型和组成型活化形式的转基因小鼠。表达高水平野生型或活化RhoA的转基因阳性小鼠表现出明显的心房扩大，并表现出致命的表型，通常在全身水肿之前，大多数动物在几周内死亡。超声心动图分析明显健康的野生型RhoA转基因小鼠显示左心室功能没有显着变化。随着病情恶化，检测到左心室腔显著扩张和左心室收缩力相关降低。心率在野生型和活化的RhoA表达小鼠中均显著降低，甚至在心室衰竭发作之前。心电图显示房颤和房室传导阻滞的证据。有趣的是，用阿托品阻断毒蕈碱受体并没有在转基因小鼠中引起正性变时性反应。我们认为RhoA调节心脏窦和房室结功能，并且其过表达会导致心动过缓和心室衰竭的发展。
RhoA is a low-molecular-weight GTPase that has been implicated in the regulation of hypertrophic cardiac muscle cell growth. To study the role of RhoA in control of cardiac function in vivo, transgenic mice expressing wild-type and constitutively activated forms of RhoA under the control of the cardiac-specific a-myosin heavy chain promoter were generated. Transgene-positive mice expressing high levels of either wild-type or activated RhoA showed pronounced atrial enlargement and manifested a lethal phenotype, often preceded by generalized edema, with most animals dying over the course of a few weeks. Echocardiographic analysis of visibly healthy wild-type RhoA transgenic mice revealed no significant change in left ventricular function. As their condition deteriorated, significant dilation of the left ventricular chamber and associated decreases in left ventricular contractility were detected. Heart rate was grossly depressed in both wild-type and activated RhoA-expressing mice, even prior to the onset of ventricular failure. Electrocardiography showed evidence of atrial fibrillation and atrioventricular block. Interestingly, muscarinic receptor blockade with atropine did not elicit a positive chronotropic response in the transgenic mice. We suggest that RhoA regulates cardiac sinus and atrioventricular nodal function and that its overexpression results in bradycardia and development of ventricular failure.