ZAK induces cardiomyocyte hypertrophy and brain natriuretic peptide expression via p38/JNK signaling and GATA4/c-Jun transcriptional factor activation
ZAK induces cardiomyocyte hypertrophy and brain natriuretic peptide expression via p38/JNK signaling and GATA4/c-Jun transcriptional factor activation
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DOI：
10.1007/s11010-015-2389-z
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发表时间：
2015-07-01
影响因子：
4.3
通讯作者：
Huang, Chih-Yang
中科院分区：
文献类型：
--
作者：
Hsieh, You-Liang;Tsai, Ying-Lan;Huang, Chih-Yang
心肌肥大是心脏对各种应激状态的适应性反应。在应激积累期，生理性肥厚向病理性肥厚过渡，导致心力衰竭的发生。我们以前的研究发现，Zak是一种无菌的α基序和亮氨酸拉链的激酶，在脑梗塞的人心脏中高度表达，并证明了Zak的过度表达导致了心肌肥厚。本研究评估了两种强力霉素(Dox)诱导的Tet-on Zak表达系统、Tet-on Zak WT(野生型)和Tet-on Zak Dn(突变，显性-阴性形式)在H9c2成肌细胞中表达的相关细胞事件；Tet-on Zak WT被发现以剂量依赖的方式增加细胞尺寸和肥大标志物BNP。为了明确ZAK介导的肥大的机制，用不同的抑制剂对相关的上下游蛋白进行了表达分析。Tet-on Zak WT的表达触发了p38和JNK途径，也激活了p-GATA4和p-c-jun转录因子的表达和核转位，而不涉及p-ERK或NFATc3。然而，Tet-on Zak DN对p38和JNK信号级联无影响。结果表明，JNK1/2和p38抑制剂可显著抑制Zak诱导的BNP表达。结果表明，ZAK和/或ZAK下游事件如JNK和p38磷酸化、c-Jun和GATA-4核转位在心肌肥厚中的作用。因此，ZAK和/或ZAK下游p38和JNK通路可能成为改善ZAK过表达患者心肌肥大症状的潜在靶点。
Cardiomyocyte hypertrophy is an adaptive response of heart to various stress conditions. During the period of stress accumulation, transition from physiological hypertrophy to pathological hypertrophy results in the promotion of heart failure. Our previous studies found that ZAK, a sterile alpha motif and leucine zipper containing kinase, was highly expressed in infarcted human hearts and demonstrated that overexpression of ZAK induced cardiac hypertrophy. This study evaluates, cellular events associated with the expression of two doxycycline (Dox) inducible Tet-on ZAK expression systems, a Tet-on ZAK WT (wild-type), and a Tet-on ZAK DN (mutant, Dominant-negative form) in H9c2 myoblast cells; Tet-on ZAK WT was found to increase cell size and hypertrophic marker BNP in a dose-dependent manner. To ascertain the mechanism of ZAK-mediated hypertrophy, expression analysis with various inhibitors of the related upstream and downstream proteins was performed. Tet-on ZAK WT expression triggered the p38 and JNK pathway and also activated the expression and nuclear translocation of p-GATA4 and p-c-Jun transcription factors, without the involvement of p-ERK or NFATc3. However, Tet-on ZAK DN showed no effect on the p38 and JNK signaling cascade. The results showed that the inhibitors of JNK1/2 and p38 significantly suppressed ZAK-induced BNP expression. The results show the role of ZAK and/or the ZAK downstream events such as JNK and p38 phosphorylation, c-Jun, and GATA-4 nuclear translocation in cardiac hypertrophy. ZAK and/or the ZAK downstream p38, and JNK pathway could therefore be potential targets to ameliorate cardiac hypertrophy symptoms in ZAK-overexpressed patients.