Integrin Activation in the Heart: A Link Between Electrical and Contractile Dysfunction?
Integrin Activation in the Heart: A Link Between Electrical and Contractile Dysfunction?
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DOI：
10.1161/01.res.0000252291.88540.ac
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发表时间：
2006-12
影响因子：
20.1
通讯作者：
M. Valencik;Dongfang Zhang;B. Punske;P. Hu;J. McDonald;S. Litwin
中科院分区：
文献类型：
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作者：
M. Valencik;Dongfang Zhang;B. Punske;P. Hu;J. McDonald;S. Litwin
在心肌细胞中，整合素将细胞骨架机械地连接到细胞外基质，从而参与机械转导。整合素似乎是心肌细胞肥大所必需的。为了确定增加的整联蛋白连接和信号传导对成年心脏功能的影响，在小鼠中条件性表达心脏特异性截短的α5整联蛋白（功能获得）。4天后，我们观察到QRS波群振幅降低80%，严重的收缩功能障碍，连接蛋白43减少，间隙连接丢失和闰盘异常。令人惊讶的是，分离的左心室肌细胞正常收缩，并表现出正常的Ca 2+瞬变。这表明细胞/细胞电和/或机械耦合被破坏。为了区分电与机械耦合缺陷，我们比较了电刺激与快速冷却收缩产生的乳头肌力，其中细胞内Ca 2+释放而无电去极化。两者在转基因肌肉中均降低。然而，电刺激收缩比快速冷却收缩更显着减少。这表明细胞/细胞电解偶联的成分。光学映射显示正常的椭圆等时激活模式的损失，这意味着通过间隙连接的优先传导的损失。这是第一次，我们已经表明，整合素可以调节机械和电气耦合在成人心脏，即使在没有主要的血流动力学改变。此外，我们证明，不受调节的整合素激活导致收缩功能障碍和心律失常。
Integrins mechanically link the cytoskeleton to the extracellular matrix in cardiac myocytes and are thereby involved in mechanotransduction. Integrins appear to be necessary for cardiac myocyte hypertrophy. To determine the effect of increased integrin ligation and signaling on adult cardiac function, a heart-specific truncated α5 integrin (gain of function) was conditionally expressed in mice. Four days later, we observed an 80% reduction in amplitude of the QRS complex, profound systolic dysfunction, decreased connexin43, loss of gap junctions, and abnormal intercalated discs. Surprisingly, isolated left ventricular myocytes contracted normally and exhibited normal Ca2+ transients. This suggested that cell/cell electrical and/or mechanical coupling was disrupted. To distinguish electrical from mechanical coupling deficits, we compared the papillary muscle force generated by electrically stimulated versus rapid cooling contractions in which intracellular Ca2+ is released without electrical depolarization. Both were decreased in the transgenic muscle. However, electrically stimulated contractions were more significantly reduced than rapid cooling contractures. This suggests a component of cell/cell electrical uncoupling. Optical mapping revealed a loss of the normal elliptical isochronal activation pattern implying a loss of preferential conduction through gap junctions. For the first time, we have shown that integrins can regulate both mechanical and electrical coupling in the adult heart, even in the absence of primary hemodynamic alterations. Furthermore, we demonstrated that unregulated integrin activation leads to both contractile dysfunction and arrhythmias.