title: ZAK induces cardiomyocyte hypertrophy and brain natriuretic peptide expression via p38/JNK signaling and GATA4/c-Jun transcriptional factor activation.
abstract: 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.
authors: Department of Health and Nutrition Biotechnology, Asia University, Taichung, Taiwan.
authors: You-Liang
authors: YL
authors: Hsieh
authors: Ying-Lan
authors: YL
authors: Tsai
authors: Marthandam Asokan
authors: MA
authors: Shibu
authors: Chia-Chi
authors: CC
authors: Su
authors: Li-Chin
authors: LC
authors: Chung
authors: Peiying
authors: P
authors: Pai
authors: Chia-Hua
authors: CH
authors: Kuo
authors: Yu-Lan
authors: YL
authors: Yeh
authors: Vijaya Padma
authors: VP
authors: Viswanadha
authors: Chih-Yang
authors: CY
authors: Huang
mesh_terms: D000818:Animals; D006332:Cardiomegaly / Q000378:metabolism* / Q000473:pathology; D002460:Cell Line; D048429:Cell Size; D050991:GATA4 Transcription Factor / Q000378:metabolism*; D020935:MAP Kinase Signaling System / Q000502:physiology*; D032383:Myocytes, Cardiac / Q000378:metabolism* / Q000473:pathology; D020097:Natriuretic Peptide, Brain / Q000378:metabolism*; D010766:Phosphorylation / Q000502:physiology; D011494:Protein Kinases / Q000378:metabolism*; D016755:Proto-Oncogene Proteins c-jun / Q000378:metabolism*; D051381:Rats; D015398:Signal Transduction / Q000502:physiology; D014157:Transcription Factors / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*; D020930:MAP Kinase Kinase Kinases
chemical_list: D050991:GATA4 Transcription Factor; D020097:Natriuretic Peptide, Brain; D011494:Protein Kinases; D016755:Proto-Oncogene Proteins c-jun; D014157:Transcription Factors; D048051:p38 Mitogen-Activated Protein Kinases; C084365:Gata4 protein, rat; C542928:Map3k20 protein, rat; D020930:MAP Kinase Kinase Kinases