ISSN: 1449-2288International Journal of Biological Sciences
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Int J Biol Sci 2020; 16(8):1335-1348. doi:10.7150/ijbs.41130 This issue Cite
Research Paper
TBC1D25 Regulates Cardiac Remodeling Through TAK1 Signaling Pathway
1. Department of Cardiology, The First Affiliated Hospital of Zhengzhou University, No.1 Jianshe East Road, Zhengzhou, China
2. Henan Key Laboratory for Esophageal Cancer Research, the First Affiliated Hospital of Zhengzhou University
3. Department of Electrocardiogram, The Second Affiliated Hospital of Zhengzhou University, No.2 Jingba Road, Zhengzhou, China
4. Department of Cardiology, The First Affiliated Hospital, and College of Clinical Medicine of Henan University of Science and Technology, Luoyang, China.
*These authors contributed equally to this work.
Abstract
Cardiac remodeling is a major early event of heart failure, which is regulated by multiple signaling pathways. Here, we demonstrate that TBC1D25 is upregulated during pathological cardiac remodeling. The aim of this study is to determine the role of TBC1D25 in cardiac remodeling and to illustrate the underlying molecular mechanism. Specifically, cardiac remodeling was induced in TBC1D25-KO mice and their wild-type control mice through partial transverse aortic constriction (TAC) of aortic arch. Knockout TBC1D25 exacerbated cardiac hypertrophy, fibrosis and dysfunction. Meanwhile, TBC1D25 overexpression in both H9C2 cells and NRCMs alleviate Angiotensin II-induced cardiomyocyte hypertrophy in vitro. Moreover, TBC1D25 deficiency increases the phosphorylation levels of TAK1 and its downstream molecular (JNK and p38), whereas overexpressed TBC1D25 inhibits phosphorylation of TAK1, JNK and p38. And TAK1 is the key molecule in this process. Furthermore, we demonstrated that TBC1D25 could directly interacts with TAK1 by immunoprecipitation assay and GST pull-down assay, and the interaction needs the amino acids from at least 138 to 226 in the C-terminal region of TBC1D25 and from 1 to 300 in the C-terminal region of TAK1. We conclude that TBC1D25 suppresses pathological cardiac remodeling via regulating TAK1-JNK/p38 signaling pathway, which suggests that TBC1D25 will likely become a promising therapeutic target for heart failure.
Keywords: cardiac remodeling, TBC1D25, TAK1, signaling pathway
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