Chronic ventricular myocyte-specific overexpression of angiotensin II type 2 receptor results in intrinsic myocyte contractile dysfunction
Chronic ventricular myocyte-specific overexpression of angiotensin II type 2 receptor results in intrinsic myocyte contractile dysfunction
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DOI：
10.1152/ajpheart.00957.2003
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发表时间：
2005-01-01
影响因子：
4.8
通讯作者：
Lorell, BH
中科院分区：
文献类型：
--
作者：
Nakayama, M;Yan, XH;Lorell, BH
血管紧张素Ⅱ 2型受体（AT（2））在衰竭心脏中上调，但其对心肌细胞收缩功能的影响尚不清楚。我们测量了来自转基因小鼠的左心室肌细胞的细胞缩短分数和细胞内Ca 2+浓度瞬变，其中AT（2）的心室特异性表达由肌球蛋白轻链2 v启动子驱动。共聚焦显微镜研究证实了心室肌细胞中AT（2）的上调以及AT（2）与AT（1）的部分共定位。研究了收缩性能的三个组成部分。首先，基线测量（0.5 Hz，1.5 mmol/l细胞外Ca 2+浓度，25 ℃）和在更快起搏频率（1-5 Hz）下的收缩储备研究显示AT（2）转基因小鼠的肌细胞中存在Ca 2+依赖性收缩功能障碍。两个转基因株系的比较表明，收缩功能障碍的程度和AT（2）表达水平之间存在剂量依赖关系。第二，Na+/H+交换器的活性，一个占主导地位的转运，调节节拍到节拍的细胞内pH值，在转基因心肌细胞受损。第三，对β-肾上腺素能与ANG II刺激的变力反应不同。两条线都表现出对β-肾上腺素能刺激的收缩反应受损。ANG Ⅱ引起野生型心肌细胞收缩力和细胞内Ca ~（2+）增加，但在AT（2）转基因小鼠的心肌细胞中引起负性肌力作用。与β-肾上腺素能反应相反，对ANG Ⅱ的抑制反应与AT（2）过表达水平有关。在心力衰竭发生之前，年轻转基因小鼠的肌细胞中也存在对ANG II的抑制反应。因此，AT（2）的慢性过度表达有可能导致心室肌细胞Ca 2+和pH依赖性收缩功能障碍，以及对ANG II的正性肌力反应丧失。
ANG II type 2 receptor (AT(2)) is upregulated in failing hearts, but its effect on myocyte contractile function is not known. We measured fractional cell shortening and intracellular Ca2+ concentration transients in left ventricular myocytes derived from transgenic mice in which ventricle-specific expression of AT(2) was driven by the myosin light chain 2v promoter. Confocal microscopy studies confirmed upregulation of AT(2) in the ventricular myocytes and partial colocalization of AT(2) with AT(1). Three components of contractile performance were studied. First, baseline measurements (0.5 Hz, 1.5 mmol/l extracellular Ca2+ concentration, 25degreesC) and study of contractile reserve at faster pacing rates (1-5 Hz) revealed Ca2+-dependent contractile dysfunction in myocytes from AT(2) transgenic mice. Comparison of two transgenic lines suggested a dose-dependent relationship between magnitude of contractile dysfunction and level of AT(2) expression. Second, activity of the Na+/H+ exchanger, a dominant transporter that regulates beat-to-beat intracellular pH, was impaired in the transgenic myocytes. Third, the inotropic response to beta-adrenergic versus ANG II stimulation differed. Both lines showed impaired contractile response to beta-adrenergic stimulation. ANG II elicited an increase in contractility and intracellular Ca2+ in wild-type myocytes but caused a negative inotropic effect in myocytes from AT(2) transgenic mice. In contrast with beta-adrenergic response, the depressed response to ANG II was related to level of AT(2) overexpression. The depressed response to ANG II was also present in myocytes from young transgenic mice before development of heart failure. Thus chronic overexpression of AT(2) has the potential to cause Ca2+- and pH-dependent contractile dysfunction in ventricular myocytes, as well as loss of the inotropic response to ANG II.