TRB3 function in cardiac endoplasmic reticulum stress.
TRB3 function in cardiac endoplasmic reticulum stress.
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DOI：
10.1161/circresaha.109.211920
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发表时间：
2010-05-14
影响因子：
20.1
通讯作者：
Muslin AJ
中科院分区：
文献类型：
--
作者：
Avery J;Etzion S;DeBosch BJ;Jin X;Lupu TS;Beitinjaneh B;Grand J;Kovacs A;Sambandam N;Muslin AJ
Tribbles 3（TRB 3）是一种细胞内假激酶，其调节几个信号转导级联的活性。据报道TRB3抑制Akt蛋白激酶的活性。TRB3基因表达在许多细胞类型中受到高度调节，并且氨基酸饥饿、缺氧或内质网（ER）应激促进TRB3在非心脏细胞中的表达。本研究的目的是检测TRB3在培养的心肌细胞和小鼠心脏中的表达和功能。诱导ER应激的药物增加了培养的心肌细胞中TRB3的表达，同时阻断了这些细胞中胰岛素刺激的Akt活化。在培养的心肌细胞中TRB3的敲低逆转了ER应激对胰岛素信号传导的影响。实验性心肌梗死导致TRB3在梗死边缘区小鼠心脏组织中表达增加，表明ER应激可能在病理性心脏重塑中起作用。产生了心脏特异性过表达TRB3的转基因小鼠，它们表现出正常的收缩功能，但改变了心脏信号转导和代谢，降低了心脏葡萄糖氧化速率。转基因TRB3小鼠也对心肌梗死后梗死边缘区的梗死扩展和心肌细胞凋亡敏感。这些结果表明，TRB3诱导是心肌细胞中ER应激反应的重要方面，TRB3拮抗心脏葡萄糖代谢和心肌细胞存活。
Tribbles 3 (TRB3) is an intracellular pseudokinase that modulates the activity of several signal transduction cascades. TRB3 has been reported to inhibit the activity of Akt protein kinases. TRB3 gene expression is highly regulated in many cell types, and amino acid starvation, hypoxia, or endoplasmic reticulum (ER) stress promotes TRB3 expression in non-cardiac cells. The objective of this work was to examine TRB3 expression and function in cultured cardiac myocytes and in mouse heart. Agents that induced ER stress increased TRB3 expression in cultured cardiac myocytes while blocking insulin-stimulated Akt activation in these cells. Knockdown of TRB3 in cultured cardiac myocytes reversed the effects of ER stress on insulin signaling. Experimental myocardial infarction led to increased TRB3 expression in murine heart tissue in the infarct border zone suggesting that ER stress may play a role in pathological cardiac remodeling. Transgenic mice with cardiac-specific overexpression of TRB3 were generated and they exhibited normal contractile function but altered cardiac signal transduction and metabolism with reduced cardiac glucose oxidation rates. Transgenic TRB3 mice were also sensitized to infarct expansion and cardiac myocyte apoptosis in the infarct border zone after myocardial infarction. These results demonstrate that TRB3 induction is a significant aspect of the ER stress response in cardiac myocytes and that TRB3 antagonizes cardiac glucose metabolism and cardiac myocyte survival.