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.

Activation of the Classical Mitogen-Activated Protein Kinases Is Part of the Shiga Toxin-Induced Ribotoxic Stress Response and May Contribute to Shiga Toxin-Induced Inflammation

“…In addition to being activated by Stx-and ricin-mediated ribotoxic stress, ZAK signaling and/or expression also has been associated with cardiac hypertrophy (45,46); G 2 /M cell cycle arrest in response to gamma irradiation (47); metastasis (48); gastric, colon, and bladder cancers (49,50); doxorubicin toxicity (51); anisomycin treatment; exposure to UV irradiation (26); osmotic shock (52); and oxidative stress (53), suggesting that ZAK transduces a number of different stress responses.…”

ZAKβ antagonizes and ameliorates the cardiac hypertrophic and apoptotic effects induced by ZAKα

“…Apoptosis has been associated with several cardiac diseases, including MI and heart failure, implying that induction of the apoptosis pathway participates in cardiac hypertrophy that subsequently progresses to cardiac dysfunction . Previous reports from our laboratory identified two main types of cardiac apoptosis, a FAS‐dependent pathway and a mitochondria‐dependent pathway, which were increased in hypertrophy and hypertension. Therefore, we examined whether ZAKα and ZAKβ potentially regulate the activation of apoptosis.…”

“…According to a previous report, the cardiac IGFIR/PI3K/Akt survival pathway may provide multiple benefits to cardiac hypertrophy. To investigate the survival pathway after ZAKα and ZAKβ induction, we measured the expression of pro‐survival‐related proteins in H9c2 cells.…”

“…ERKs are more specialized for growth and mitogenic stimulation . ERK‐involved signaling is initiated at the cell membrane in cooperation with Ras activation and direct coordination with the MAPK kinase MEK1/MEK2 . By contrast, JNK and p38 kinases are involved in transduction during injury response or stress .…”

Overexpression of ZAKβ in human osteosarcoma cells enhances ZAKα expression, resulting in a synergistic apoptotic effect

“…7 In hippocampal CA1 neurons, the ZAKα protein level was increased after injury. [10][11][12] However, the role of ZAKβ is still unclear, although some studies have focused on ZAKβ. 9 These studies have led many scientists to believe that ZAKα may play an oncogenic role in promoting tumour development.…”