Hypertrophy and heart failure in mice overexpressing the cardiac sodium-calcium exchanger
Hypertrophy and heart failure in mice overexpressing the cardiac sodium-calcium exchanger
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DOI：
10.1016/j.cardfail.2007.01.004
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发表时间：
2007-05-01
影响因子：
6
通讯作者：
Philipson, Kenneth D.
中科院分区：
文献类型：
--
作者：
Roos, Kenneth P.;Jordan, Maria C.;Philipson, Kenneth D.
背景：心脏钠钙交换器（NCX1）是维持心脏钙稳态的关键肌膜蛋白。由于心力衰竭与 NCX1 表达增加相关，因此开发并评估了过度表达 NCX1 的杂合 (HET) 和纯合 (HOM) 转基因小鼠。 方法和结果：NCX1 转基因小鼠的交换活性比野生型 (WT) 小鼠增加了 2.3 倍 (HET) 和 3.1 倍 (HOM)。通过超声心动图和导管插入术在妊娠、跑步机运动或经主动脉缩窄（TAC）造成的血流动力学应激前后获得功能信息。 HET 和 HOM 小鼠表现出肥大和对 β-肾上腺素能刺激的反应减弱。所有组的产后小鼠均出现肥大，但只有 HOM 小鼠因心力衰竭而过早死亡。 HOM 小鼠在每天跑步机跑步 6 周后变得不耐受。 21天后，TAC、HET和HOM小鼠表现出明显的收缩功能障碍，死亡率为15%至40%，并有心力衰竭的临床证据。结论：血流动力学应激导致WT小鼠代偿性肥大，但NCX1转基因小鼠表现出与其NCX1表达水平成比例的收缩功能下降和心力衰竭。因此，小鼠中交换器的过度表达会导致钙处理异常，并失代偿性地转变为应激性心力衰竭。
Background: The cardiac sodium-calcium exchanger (NCX1) is a key sarcolemmal protein for the maintenance of calcium homeostasis in the heart. Because heart failure is associated with increased expression of NCX1, heterozygous (HET) and homozygous (HOM) transgenic mice overexpressing NCX1 were developed and evaluated.Methods and Results: The NCX1 transgenic mice display 2.3-fold (HET) and 3.1-fold (HOM) increases in exchanger activity from wild-type (WT) mice. Functional information was obtained by echocardiography and catheterizations before and after hemodynamic stress from pregnancy, treadmill exercise or transaortic constriction (TAC). HET and HOM mice exhibited hypertrophy and blunted responses with beta-adrenergic stimulation. Postpartum mice from all groups were hypertrophied, but only the HOM mice exhibited premature death from heart failure. HOM mice became exercise intolerant after 6 weeks of daily treadmill running. After 21 days TAC, HET, and HOM mice exhibited significant contractile dysfunction and 15% to 40% mortality with clinical evidence of heart failure.Conclusions: Hemodynamic stress results in a compensated hypertrophy in WT mice, but NCX1 transgenic mice exhibit decreased contractile function and heart failure in proportion to their level of NCX1 expression. Thus exchanger overexpression in mice leads to abnormal calcium handling and a decompensatory transition to heart failure with stress.