Partial Inactivation of Cardiac 14-3-3 Protein in vivo Elicits Endoplasmic Reticulum Stress (ERS) and Activates ERS-initiated Apoptosis in ERS-induced Mice
Partial Inactivation of Cardiac 14-3-3 Protein in vivo Elicits Endoplasmic Reticulum Stress (ERS) and Activates ERS-initiated Apoptosis in ERS-induced Mice
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DOI：
10.1159/000320548
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发表时间：
2006-01
影响因子：
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通讯作者：
Flori R. Sari;Kenichi Watanabe;B. Widyantoro;R. Thandavarayan;Meilei Harima;Shaosong Zhang;Anthony J. Muslin;M. Kodama;Y. Aizawa
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文献类型：
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作者：
Flori R. Sari;Kenichi Watanabe;B. Widyantoro;R. Thandavarayan;Meilei Harima;Shaosong Zhang;Anthony J. Muslin;M. Kodama;Y. Aizawa
背景/目的：过度的内质网应激(ERS)可在多种情况下触发细胞凋亡，包括糖尿病心肌病和压力超负荷所致的心肌肥厚和心力衰竭。14-3-3蛋白的主要功能是抑制细胞凋亡，但该蛋白在保护心脏ERS和细胞凋亡中的作用尚不清楚。方法：利用心脏特异表达14-3-3η的转基因(TG)小鼠，研究14-3-3蛋白在心脏ERS和压力超负荷或注射thapsigargin诱导的细胞凋亡中的作用。结果：与WT小鼠相比，压力超负荷诱导的DN14-3-3η小鼠心肌细胞凋亡阳性细胞数和葡萄糖调节蛋白78、肌醇需要酶1、肿瘤坏死因子受体相关因子2、CCAAT/增强子结合蛋白同源蛋白、半胱氨酸天冬氨酸蛋白酶12和裂解半胱氨酸天冬氨酸蛋白酶12蛋白的表达均显著增加。此外，与WT小鼠相比，thapsigargin注射显著上调了DN14-3-3η小鼠GRP78和TRAF2的表达。结论：14-3-3蛋白的增强可能通过IRE1α/TRAF2途径调节CHOP和Caspase-12，从而为心脏ERS和ERS诱导的细胞凋亡提供一种新的保护措施。
Background/Aims: Excessive endoplasmic reticulum stress (ERS) triggers apoptosis in various conditions including diabetic cardiomyopathy and pressure overload-induced cardiac hypertrophy and heart failure. The primary function of 14-3-3 protein is to inhibit apoptosis, but the roles of this protein in protecting against cardiac ERS and apoptosis are largely unknown. Methods: We investigated the roles of 14-3-3 protein in vivo during cardiac ERS and apoptosis induced by pressure overload or thapsigargin injection using transgenic (TG) mice that showed cardiac-specific expression of dominant negative (DN) 14-3-3η. Results: Cardiac positive apoptotic cells and the expression of glucose-regulated protein (GRP)78, inositol-requiring enzyme (Ire)1α, tumor necrosis factor receptor (TNFR)-associated factor (TRAF)2, CCAAT/enhancer binding protein homology protein (CHOP), caspase-12, and cleaved caspase-12 protein were significantly increased in the pressure-overload induced DN 14-3-3η mice compared with that in the WT mice. Furthermore, thapsigargin injection significantly increased the expression of GRP78 and TRAF2 expression in DN 14-3-3η mice compared with that in the WT mice. Conclusion: The enhancement of 14-3-3 protein may provide a novel protective therapy against cardiac ERS and ERS-initiated apoptosis, at least in part, through the regulation of CHOP and caspase-12 via the Ire1α/TRAF2 pathway.