Overexpression of angiotensin II type I receptor in cardiomyocytes induces cardiac hypertrophy and remodeling
Overexpression of angiotensin II type I receptor in cardiomyocytes induces cardiac hypertrophy and remodeling
复制标题
DOI：
10.1073/pnas.97.2.931
复制
发表时间：
2000-01-18
影响因子：
11.1
通讯作者：
Nemer, M
中科院分区：
文献类型：
--
作者：
Paradis, P;Dali-Youcef, N;Nemer, M
血管紧张素II （AII）是动脉压力和容量稳态的主要决定因素，主要是因为其通过All型1受体（AT1R）的血管作用，All也与心脏肥厚的发展有关，因为血管紧张素i转换酶抑制剂和AT1R拮抗剂在动物模型和人类中可预防或逆转心室肥厚。然而，由于这些治疗阻碍了All在心脏和血管水平的作用，并降低了血压，因此很难确定AII对心脏的作用是直接的还是压力过载的结果。为了确定AII是否可以在没有血管改变的情况下直接通过心肌AT1R诱导心肌肥厚，我们在小鼠α -肌球蛋白重链启动子的控制下，产生过表达人AT1R的转基因小鼠。在基础条件下，心肌细胞特异性过表达AT1R诱导心肌细胞和非心肌细胞的形态变化，类似于人类和其他哺乳动物心肌肥厚发展过程中观察到的变化。这些小鼠表现出明显的心脏肥大和重构，心室房利钠因子表达和间质胶原沉积增加，并因心力衰竭而过早死亡。收缩压和心率都没有变化。这些数据表明AII在心肌肥厚和心力衰竭的发展中具有直接的心肌作用，并为阐明AII在心脏病发病机制中的作用机制提供了有用的模型。
Angiotensin II (AII) is a major determinant of arterial pressure and volume homeostasis, mainly because of its vascular action via the All type 1 receptor (AT1R), All has also been implicated in the development of cardiac hypertrophy because angiotensin I-converting enzyme inhibitors and AT1R antagonists prevent or regress ventricular hypertrophy in animal models and in human. However, because these treatments impede the action of All at cardiac as well as vascular levels, and reduce blood pressure, it has been difficult to determine whether AII action on the heart is direct or a consequence of pressure-overload. To determine whether AII can induce cardiac hypertrophy directly via myocardial AT1R in the absence of vascular changes, transgenic mice overexpressing the human AT1R under the control of the mouse alpha-myosin heavy chain promoter were generated. Cardiomyocyte-specific overexpression of AT1R induced, in basal conditions, morphologic changes of myocytes and nonmyocytes that mimic those observed during the development of cardiac hypertrophy in human and in other mammals. These mice displayed significant cardiac hypertrophy and remodeling with increased expression of ventricular atrial natriuretic factor and interstitial collagen deposition and died prematurely of heart failure. Neither the systolic blood pressure nor the heart rate were changed. The data demonstrate a direct myocardial role for AII in the development of cardiac hypertrophy and failure and provide a useful model to elucidate the mechanisms of action of AII in the pathogenesis of cardiac diseases.