Ablation of C/EBP Homologous Protein Attenuates Endoplasmic Reticulum-Mediated Apoptosis and Cardiac Dysfunction Induced by Pressure Overload
Ablation of C/EBP Homologous Protein Attenuates Endoplasmic Reticulum-Mediated Apoptosis and Cardiac Dysfunction Induced by Pressure Overload
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DOI：
10.1161/circulationaha.109.917914
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发表时间：
2010-07-27
期刊：
影响因子：
37.8
通讯作者：
Minamino, Tetsuo
中科院分区：
文献类型：
--
作者：
Fu, Hai Ying;Okada, Ken-ichiro;Minamino, Tetsuo
背景-细胞凋亡可能有助于心力衰竭的发展，但内质网启动的细胞凋亡信号在这种情况下的作用还没有得到很好的澄清。方法和结果-在心力衰竭患者的心肌样本中，定量实时聚合酶链反应显示C/EBP同源蛋白（CHOP）的信使RNA增加，一种介导内质网引发的凋亡性细胞死亡的转录因子。我们对野生型（WT）和CHOP缺陷小鼠进行了主动脉横缩窄或假手术。在横向主动脉缩窄后4周，CHOP缺陷小鼠与WT小鼠相比，心脏肥大、纤维化和心功能障碍较少，尽管CHOP缺陷小鼠的分离心肌细胞的收缩性与WT小鼠无显著差异。在CHOP缺陷小鼠的心脏中，与WT小鼠相比，真核翻译起始因子2 α的磷酸化增强，这可能会减少蛋白质翻译。在WT小鼠的心脏中，在主动脉横向收缩后4周观察到CHOP增加了细胞凋亡死亡，并激活了caspase-3。相比之下，CHOP缺陷小鼠在主动脉横缩窄后4周时凋亡细胞死亡较少，caspase-3活化较低。此外，Bcl 2/Bax比率在WT小鼠中降低，而这种变化在CHOP缺陷小鼠中显著减弱。实时聚合酶链反应微阵列分析显示，CHOP可以调节几个Bcl 2家族成员在失败hearts. Conclusions，我们提出了新的概念，CHOP，这可能会修改蛋白质翻译和介导内质网启动的凋亡细胞死亡，有助于发展的心脏肥大和压力超负荷引起的衰竭。（循环。2010;122：361-369）。
Background-Apoptosis may contribute to the development of heart failure, but the role of apoptotic signaling initiated by the endoplasmic reticulum in this condition has not been well clarified.Methods and Results-In myocardial samples from patients with heart failure, quantitative real-time polymerase chain reaction revealed an increase in messenger RNA for C/EBP homologous protein (CHOP), a transcriptional factor that mediates endoplasmic reticulum-initiated apoptotic cell death. We performed transverse aortic constriction or sham operation on wild-type (WT) and CHOP-deficient mice. The CHOP-deficient mice showed less cardiac hypertrophy, fibrosis, and cardiac dysfunction compared with WT mice at 4 weeks after transverse aortic constriction, although the contractility of isolated cardiomyocytes from CHOP-deficient mice was not significantly different from that in the WT mice. In the hearts of CHOP-deficient mice, phosphorylation of eukaryotic translation initiation factor 2 alpha, which may reduce protein translation, was enhanced compared with WT mice. In the hearts of WT mice, CHOP-increased apoptotic cell death with activation of caspase-3 was observed at 4 weeks after transverse aortic constriction. In contrast, CHOP-deficient mice had less apoptotic cell death and lower caspase-3 activation at 4 weeks after transverse aortic constriction. Furthermore, the Bcl2/Bax ratio was decreased in WT mice, whereas this change was significantly blunted in CHOP-deficient mice. Real-time polymerase chain reaction microarray analysis revealed that CHOP could regulate several Bcl2 family members in failing hearts.Conclusions-We propose the novel concept that CHOP, which may modify protein translation and mediate endoplasmic reticulum-initiated apoptotic cell death, contributes to development of cardiac hypertrophy and failure induced by pressure overload. (Circulation. 2010;122:361-369.)