Engelhardt Stefan, Hein Lutz, Keller Ursula, Klämbt Kerstin, Lohse Martin J
Institut für Pharmakologie und Toxikologie, Universität Würzburg, Germany.
Circ Res. 2002 Apr 19;90(7):814-9. doi: 10.1161/01.res.0000014966.97486.c0.
Chronic stimulation of the beta(1)-adrenergic receptor leads to hypertrophy and heart failure in beta(1)-adrenergic receptor transgenic mice and contributes to disease progression in heart failure patients. The cellular mechanisms underlying these detrimental effects are largely unknown. In this study, we have identified the cardiac Na(+)-H(+) exchanger (NHE1) as a novel mediator of adrenergically induced heart failure. beta(1)-Adrenergic receptor transgenic mice showed upregulation of both NHE1 mRNA (+140+/-6%) and protein (+42+/-19%). In order to test whether increased NHE1 is causally related to beta(1)-adrenergic-induced hypertrophy, fibrosis, and heart failure, beta(1)-adrenergic receptor transgenic (TG) and wild-type (WT) littermates were treated with a diet containing 6000 ppm of the NHE1 inhibitor cariporide or control chow for 8 months. There was significant hypertrophy of cardiac myocytes in beta(1)-adrenergic receptor transgenic mice (2.3-fold increase in myocyte cross-sectional area), which was virtually absent in cariporide-fed animals. Interstitial fibrosis was prominent throughout the left ventricular wall in nontreated beta(1)-adrenergic receptor transgenic mice (4.8-fold increase in collagen volume fraction); cariporide treatment completely prevented this development of fibrosis. Left ventricular catheterization showed that cariporide also prevented the loss of contractile function in beta(1)-adrenergic receptor transgenic mice: whereas untreated transgenic mice showed a significant decrease in left ventricular contractility (5250+/-570 mm Hg/s TG versus 7360+/-540 mm Hg/s WT, dp/dt(max)), this decrease was completely prevented by cariporide (8150+/-520 mm Hg/s TG cariporide). Inhibition of NHE1 prevented the development of heart failure in beta(1)-receptor transgenic mice. We conclude that the cardiac Na(+)-H(+) exchanger 1 is essential for the detrimental cardiac effects of chronic beta(1)-receptor stimulation in the heart.
在β1 - 肾上腺素能受体转基因小鼠中，慢性刺激β1 - 肾上腺素能受体会导致心肌肥大和心力衰竭，并且在心力衰竭患者疾病进展中也起作用。这些有害作用背后的细胞机制很大程度上尚不清楚。在本研究中，我们已确定心脏钠氢交换体（NHE1）是肾上腺素能诱导心力衰竭的一种新介质。β1 - 肾上腺素能受体转基因小鼠表现出NHE1 mRNA（增加140±6%）和蛋白（增加42±19%）均上调。为了测试NHE1增加是否与β1 - 肾上腺素能诱导的肥大、纤维化和心力衰竭存在因果关系，将β1 - 肾上腺素能受体转基因（TG）和野生型（WT）同窝小鼠用含6000 ppm NHE1抑制剂卡立泊来德的饮食或对照饲料处理8个月。β1 - 肾上腺素能受体转基因小鼠出现心肌细胞显著肥大（心肌细胞横截面积增加2.3倍），而在喂食卡立泊来德动物中几乎不存在。在未处理的β1 - 肾上腺素能受体转基因小鼠中，整个左心室壁间质纤维化明显（胶原体积分数增加4.8倍）；卡立泊来德治疗完全阻止了这种纤维化的发展。左心室插管显示卡立泊来德还防止了β1 - 肾上腺素能受体转基因小鼠收缩功能丧失：未处理的转基因小鼠左心室收缩性显著降低（TG为5250±570 mmHg/s，而WT为7360±540 mmHg/s，dp/dt(max)），而卡立泊来德完全阻止了这种降低（TG卡立泊来德为8150±520 mmHg/s）。抑制NHE1可防止β1 - 受体转基因小鼠心力衰竭的发展。我们得出结论，心脏钠氢交换体1对于心脏中慢性β1 - 受体刺激的有害心脏效应至关重要。
