Endocardial TRPC-6 Channels Act as Atrial Mechanosensors and Load-Dependent Modulators of Endocardial/Myocardial Cross-Talk.
Endocardial TRPC-6 Channels Act as Atrial Mechanosensors and Load-Dependent Modulators of Endocardial/Myocardial Cross-Talk.
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DOI：
10.1016/j.jacbts.2017.05.006
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发表时间：
2017-10
期刊：
影响因子：
--
通讯作者：
Fatkin D
中科院分区：
文献类型：
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作者：
Nikolova-Krstevski V;Wagner S;Yu ZY;Cox CD;Cvetkovska J;Hill AP;Huttner IG;Benson V;Werdich AA;MacRae C;Feneley MP;Friedrich O;Martinac B;Fatkin D
TRPC-6存在于人、猪和小鼠的心房内皮细胞中。内皮素TRPC-6通道作为心房机械传感器，显示响应于以时间依赖性方式施加的机械牵拉的定位、表达水平和活性的变化。心房内皮细胞发挥TRPC-6依赖性旁分泌作用，在正常生理条件下增加心肌Ca 2+瞬变的幅度。这些正性肌力作用在急性牵张的情况下丧失。内皮素TRPC-6参与调节反馈回路，急性保护对抗牵张诱导的心肌Ca 2+过载。然而，持续牵张，减少表达的endoadrenal TRPC-6和不规则的Ca 2+短暂的周期性可能有助于增加心律失常的倾向。机械电反馈可能增加心律失常的易感性，但其分子机制尚未完全了解。这项研究表明，机械拉伸改变了人类，猪和小鼠心房内膜细胞中阳离子选择性瞬时受体电位通道（TRPC）-6的定位，蛋白水平和功能。在内皮细胞/心肌串扰研究中，加入来自猪心房内皮细胞（AE）的培养基改变了人诱导的多能干细胞衍生的心肌细胞的钙（Ca 2+）瞬态特性。这些变化没有发生与媒体从拉伸AE细胞。我们的数据表明，内分泌TRPC-6依赖的旁分泌信号可能调节心肌钙稳态基础条件下，并防止牵张诱导的房性心律失常。
TRPC-6 is present in atrial endocardial endothelium in humans, pigs, and mice. Endocardial TRPC-6 channels act as atrial mechanosensors, showing changes in localization, expression levels, and activity in response to applied mechanical stretch in a time-dependent manner. The atrial endocardial endothelium exerts TRPC-6-dependent paracrine effects that increase the amplitude of myocardial Ca2+ transients under normal physiological conditions. These positive inotropic effects are lost in settings of acute stretch. Endocardial TRPC-6 participates in a regulatory feedback loop that acutely protects against stretch-induced myocardial Ca2+ overload. However, with persistent stretch, reduced expression of endocardial TRPC-6 and irregular Ca2+ transient periodicity may contribute to an increased arrhythmia propensity. Mechanoelectrical feedback may increase arrhythmia susceptibility, but the molecular mechanisms are incompletely understood. This study showed that mechanical stretch altered the localization, protein levels, and function of the cation-selective transient receptor potential channel (TRPC)-6 in atrial endocardial cells in humans, pigs, and mice. In endocardial/myocardial cross-talk studies, addition of media from porcine atrial endocardium (AE) cells altered the calcium (Ca2+) transient characteristics of human-induced pluripotent stem cell-derived cardiomyocytes. These changes did not occur with media from stretched AE cells. Our data suggested that endocardial TRPC-6-dependent paracrine signaling may modulate myocardial Ca2+ homeostasis under basal conditions and protect against stretch-induced atrial arrhythmias.