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首页> 外文期刊>American Journal of Physiology >Contractile regulation by overexpressed ET_A requires intact T tubules in adult rat ventricular myocytes
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Contractile regulation by overexpressed ET_A requires intact T tubules in adult rat ventricular myocytes

机译：过度表达的ET_A的收缩调节需要成年大鼠心室肌细胞中完整的T小管

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摘要

Endothelin (ET)-1 regulates the contractility and growth of the heart by binding G protein-coupled receptors of the ET type A receptor (ET_A)/ET type B (ET_B) receptor family. ET_A, the predominant ET-1 receptor subtype in myocardium, is thought to localize preferentially within cardiac T tubules, but the consequences of mislocalization are not fully understood. Here we examined the effects of the overexpressionof ET_A in conjunction with T-tubule loss in cultured adult rat ventricular myocytes. In adult myocytes cultured for 3 to 4 days, the normally robust positive inotropic effect (PIE) of ET-1 was lost in parallel with T-tubule degeneration and a decline in ET_A protein levels. In these T tubule-compromised myocytes, an overexpression of ET_A using an adenoviral vector did not rescue the responsiveness to ET-1, despite the robust expression in the surface sarcolemma. The inclusion of the actin polymerization inhibitor cytochalasin D (CD) during culture prevented gross morphological changes including a loss of T tubules and a rounding of intercalated discs, but CD alone did not rescue the responsiveness to ET-1 or prevent ET_A downregulation.The rescue of a normal PIE in 3- to 4-day cultured myocytes required both an increased expression of ET_A and intact T tubules (preserved with CD). Therefore, the activation of ET_A localized in T tubules was associated with a strong PIE, whereas the activation of ET_A in surface sarcolemma was not. The results provide insight into the pathological cardiac conditions in which ET_A is upregulated and T-tubule morphology is altered.
机译：内皮素（ET）-1通过结合ET A型受体（ET_A）/ B B型（ET_B）受体家族的G蛋白偶联受体来调节心脏的收缩力和生长。 ET_A是心肌中主要的ET-1受体亚型，被认为优先定位于心脏T小管内，但尚未完全了解定位错误的后果。在这里，我们检查了成年大鼠心室肌细胞中ET_A过度表达与T管丢失的关系。在培养3至4天的成年心肌细胞中，ET-1的正常强力正性肌力作用（PIE）与T管变性和ET_A蛋白水平下降同时消失。在这些T管小管受损的心肌细胞中，尽管表面肌膜中有强力表达，但使用腺病毒载体过表达ET_A并不能挽救对ET-1的反应性。在培养过程中加入肌动蛋白聚合抑制剂细胞松弛素D（CD）可以防止总体形态变化，包括T管丢失和圆盘插层变圆，但仅CD不能拯救对ET-1的反应性或阻止ET_A下调。在3至4天的培养的心肌细胞中，正常PIE的检测既需要增加ET_A的表达，又需要完整的T小管（用CD保存）。因此，位于T小管中的ET_A的激活与强PIE相关，而表面肉瘤中的ET_A的激活则不相关。结果为深入了解ET_A上调和T管形态改变的病理性心脏病提供了见识。

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