Attenuation of CHOP-mediated Myocardial Apoptosis in Pressure-overloaded Dominant Negative p38α Mitogen-activated Protein Kinase Mice
Attenuation of CHOP-mediated Myocardial Apoptosis in Pressure-overloaded Dominant Negative p38α Mitogen-activated Protein Kinase Mice
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DOI：
10.1159/000329970
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发表时间：
2011-01-01
影响因子：
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通讯作者：
Watanabe, Kenichi
中科院分区：
文献类型：
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作者：
Sari, Flori R.;Widyantoro, Bambang;Watanabe, Kenichi
背景/目的：众所周知，压力过载刺激会引起内质网 (ER) 紊乱，从而导致 ER 应激 (ERS)。 p38 丝裂原激活蛋白激酶 (MAPK) 在介导细胞凋亡过程中发挥重要作用，然而，该激酶在压力超负荷心脏中激活 ERS 引发的细胞凋亡中的作用很大程度上未知。方法：我们通过将心脏特异性显性失活（DN）突变体 p38 α MAPK 过度表达的转基因小鼠置于 7 天的压力超负荷下，阐明了 p38 α MAPK 在 ERS 相关细胞凋亡中的作用。结果：与假手术小鼠相比，7 天的压力超负荷导致野生型 (WT) 和 DN p38 α 小鼠出现相同程度的心脏肥大和 ERS。与假手术小鼠相比，它还激活了 WT 和 DN p38 α 小鼠中的肌醇需求酶 (Ire)-1 α 及其下游分子肿瘤坏死因子受体 (TNFR) 相关因子 (TRAF) 2。有趣的是，与假手术小鼠相比，在带主动脉带的WT小鼠中发现心肌细胞凋亡增加，并且CCAAT/增强子结合蛋白同源蛋白（CHOP）表达上调，但在DN p38 α小鼠中没有发现。结论：部分抑制 p38 α 蛋白通过部分抑制从 Ire-1 α/TRAF2 到其下游分子 CHOP 的信号传导，阻断压力超负荷期间 CHOP 介导的细胞凋亡过程的激活。版权所有 (C) 2011 S. Karger AG，巴塞尔
Background/Aims: Pressure overload stimulation is known to elicit disturbances in the endoplasmic reticulum (ER), which leads to ER stress (ERS). p38 mitogen-activated protein kinase (MAPK) plays an important role in mediating apoptotic processes, however, the roles of this kinase in activating ERS-initiated apoptosis in pressure-overloaded hearts are largely unknown. Methods: We clarified the role of p38 alpha MAPK in ERS-associated apoptosis by subjecting transgenic mice displaying cardiac specific dominant negative (DN) mutant p38 alpha MAPK overexpression to seven day pressure overload. Results: Seven days pressure overload resulted in the same extent of cardiac hypertrophy and ERS in the wildtype (WT) and DN p38 alpha mice compared with the sham mice. It also activated inositol-requiring enzyme (Ire)- 1 alpha and its downstream molecule, tumor necrosis factor receptor (TNFR)-associated factor (TRAF) 2 in the WT and DN p38 alpha mice compared with the sham mice. Interestingly, increased myocardial apoptosis and the up-regulation of CCAAT/enhancer binding protein homology protein (CHOP) expression compared with those in the sham mice were found in the aortic-banded WT mice, but not in the DN p38 alpha mice. Conclusion: Partial inhibition of p38 alpha protein blocked the activation of CHOP-mediated apoptotic processes during pressure overload by partially inhibiting signaling from the Ire-1 alpha/TRAF2 to its downstream molecule, CHOP. Copyright (C) 2011 S. Karger AG, Basel