CREB Negatively Regulates IGF2R Gene Expression and Downstream Pathways to Inhibit Hypoxia-Induced H9c2 Cardiomyoblast Cell Death

International Journal of Molecular Sciences

Wei-Kung Chen²  Wei-Wen Kuo⁴  Dennis Jine-Yuan Hsieh⁶  Hsin-Nung Chang⁹  Pei-Ying Pai⁵  Kuan-Ho Lin²  Lung-Fa Pan⁸  Tsung-Jung Ho¹  Vijaya Padma Viswanadha⁷  Chih-Yang Huang³ 

[1]School of Chinese Medicine, College of Chinese Medicine, China Medical University, Taichung 40402, Taiwan

[2]Department of Emergency Medicine, China Medical University Hospital, Taichung 40402, Taiwan

[3]

[4]Chinese Medicine Department, China Medical University Beigang Hospital, Yunlin 651, TaiwanDepartment of Biological Science and Technology, China Medical University, Taichung 40402, Taiwan

[5]Division of Cardiology, China Medical University Hospital, Taichung 40402, Taiwan

[6]School of Medical Laboratory and Biotechnology, Chung Shan Medical University, Taichung 40201, Taiwan

[7]Department of Biotechnology, Bharathiar University, Coimbatore-641 046, India

[8]Cardiology Department, Taichung Armed Forces General Hospital. Taichung 41152, Taiwan

[9]Graduate Institute of Clinical Medical Science, China Medical University, Taichung 40402, Taiwan

关键词: CREB;    hypoxia;    apoptosis;    IGF2R signaling;   

DOI  :  10.3390/ijms161126067

来源: mdpi

【 摘 要 】

During hypoxia, gene expression is altered by various transcription factors. Insulin-like growth factor-II (IGF2) is known to be induced by hypoxia, which binds to IGF2 receptor IGF2R that acts like a G protein-coupled receptor, might cause pathological hypertrophy or activation of the mitochondria-mediated apoptosis pathway. Cyclic adenosine monophosphate (cAMP) responsive element-binding protein (CREB) is central to second messenger-regulated transcription and plays a critical role in the cardiomyocyte survival pathway. In this study, we found that IGF2R level was enhanced in H9c2 cardiomyoblasts exposed to hypoxia in a time-dependent manner but was down-regulated by CREB expression. The over-expression of CREB in H9c2 cardiomyoblasts suppressed the induction of hypoxia-induced IGF2R expression levels and reduced cell apoptosis. Gel shift assay results further indicated that CREB binds to the promoter sequence of IGF2R. With a luciferase assay method, we further observed that CREB represses IGF2R promoter activity. These results suggest that CREB plays an important role in the inhibition of IGF2R expression by binding to the IGF2R promoter and further suppresses H9c2 cardiomyoblast cell apoptosis induced by IGF2R signaling under hypoxic conditions.

【 授权许可】

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