Cardiac troponin I gene knockout: a mouse model of myocardial troponin I deficiency.
Cardiac troponin I gene knockout: a mouse model of myocardial troponin I deficiency.
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DOI：
10.1161/01.res.84.1.1
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发表时间：
1999-01
影响因子：
20.1
通讯作者：
Xupei Huang;Y. Pi;Kevin J. Lee;Anne S Henkel;Ronald G. Gregg;P. Powers;Jeffery W. Walker
中科院分区：
文献类型：
--
作者：
Xupei Huang;Y. Pi;Kevin J. Lee;Anne S Henkel;Ronald G. Gregg;P. Powers;Jeffery W. Walker
肌钙蛋白I是与骨骼肌和心肌收缩的钙调节有关的瘦肌钙蛋白-原肌球蛋白复合物的亚基。我们通过在小鼠胚胎干细胞中使用基因靶向技术删除了心肌肌钙蛋白I亚型，以确定缺乏这种调节蛋白的发育和生理影响。缺乏心肌肌钙蛋白I的小鼠出生时健康，心脏和体重正常，因为胎儿肌钙蛋白I同种型（与缓慢骨骼肌肌钙蛋白I相同）弥补了心肌肌钙蛋白I的缺乏。然而，补偿只是暂时的，因为出生后15天，骨骼肌钙蛋白I表达缓慢开始稳步下降，导致肌钙蛋白I缺乏。小鼠在第18天死于急性心力衰竭，表明正常心脏功能和存活需要某种形式的肌钙蛋白I。从这些肌钙蛋白I耗尽的心脏中分离的心室肌细胞显示肌节缩短和静息张力升高，在放松条件下测量，并在激活条件下具有降低的肌丝Ca敏感性。结果表明：（1）即使在缺乏心肌肌钙蛋白I的情况下，骨骼肌肌钙蛋白I的发育性下调也会发生;（2）由此产生的肌钙蛋白I耗竭改变了心肌的特定机械特性，并可能导致致命形式的急性心力衰竭。
Troponin I is a subunit of the thin filament-associated troponin-tropomyosin complex involved in calcium regulation of skeletal and cardiac muscle contraction. We deleted the cardiac isoform of troponin I by using gene targeting in murine embryonic stem cells to determine the developmental and physiological effects of the absence of this regulatory protein. Mice lacking cardiac troponin I were born healthy, with normal heart and body weight, because a fetal troponin I isoform (identical to slow skeletal troponin I) compensated for the absence of cardiac troponin I. Compensation was only temporary, however, as 15 days after birth slow skeletal troponin I expression began a steady decline, giving rise to a troponin I deficiency. Mice died of acute heart failure on day 18, demonstrating that some form of troponin I is required for normal cardiac function and survival. Ventricular myocytes isolated from these troponin I-depleted hearts displayed shortened sarcomeres and elevated resting tension measured under relaxing conditions and had a reduced myofilament Ca sensitivity under activating conditions. The results show that (1) developmental downregulation of slow skeletal troponin I occurs even in the absence of cardiac troponin I and (2) the resultant troponin I depletion alters specific mechanical properties of myocardium and can lead to a lethal form of acute heart failure.