Pathological cardiac hypertrophy is an independent risk factor of heart failure. However, we still lack effective methods to reverse cardiac hypertrophy. DUSP12 is a member of the dual specific phosphatase (DUSP) family, which is characterized by its DUSP activity to dephosphorylate both tyrosine and serine/threonine residues on one substrate. Some DUSPs have been identified as being involved in the regulation of cardiac hypertrophy. However, the role of DUSP12 during pathological cardiac hypertrophy is still unclear. In the present study, we observed a significant decrease in DUSP12 expression in hypertrophic hearts and cardiomyocytes. Using a genetic loss-of-function murine model, we demonstrated that DUSP12 deficiency apparently aggravated pressure overload-induced cardiac hypertrophy and fibrosis as well as impaired cardiac function, whereas cardiac-specific overexpression of DUPS12 was capable of reversing this hypertrophic and fibrotic phenotype and improving contractile function. Furthermore, we demonstrated that JNK1/2 activity but neither ERK1/2 nor p38 activity was increased in the DUSP12 deficient group and decreased in the DUSP12 overexpression group both in vitro and in vivo under hypertrophic stress conditions. Pharmacological inhibition of JNK1/2 activity (SP600125) is capable of reversing the hypertrophic phenotype in DUSP12 knockout (KO) mice. DUSP12 protects against pathological cardiac hypertrophy and related pathologies. This regulatory role of DUSP12 is primarily through c-Jun N-terminal kinase (JNK) inhibition. DUSP12 could be a promising therapeutic target of pathological cardiac hypertrophy. DUSP12 is down-regulated in hypertrophic hearts. An absence of DUSP12 aggravated cardiac hypertrophy, whereas cardiomyocyte-specific DUSP12 overexpression can alleviate this hypertrophic phenotype with improved cardiac function. Further study demonstrated that DUSP12 inhibited JNK activity to attenuate pathological cardiac hypertrophy.
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Masson staining of rat liver specimens. Please see pp. 159-168 for more information. Image provided by Xujiong Li.
Research Article|
December 23 2016
Dual specific phosphatase 12 ameliorates cardiac hypertrophy in response to pressure overload
Wei-ming Li;
Wei-ming Li
1
*Department of Cardiology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai 200072, P.R. China
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Yi-fan Zhao;
Yi-fan Zhao
1
*Department of Cardiology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai 200072, P.R. China
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Guo-fu Zhu;
Guo-fu Zhu
*Department of Cardiology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai 200072, P.R. China
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Wen-hui Peng;
Wen-hui Peng
*Department of Cardiology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai 200072, P.R. China
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Meng-yun Zhu;
Meng-yun Zhu
*Department of Cardiology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai 200072, P.R. China
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Xue-jing Yu;
Xue-jing Yu
*Department of Cardiology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai 200072, P.R. China
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Wei Chen;
Wei Chen
*Department of Cardiology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai 200072, P.R. China
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Da-chun Xu;
Da-chun Xu
*Department of Cardiology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai 200072, P.R. China
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Ya-wei Xu
*Department of Cardiology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai 200072, P.R. China
Correspondence: Ya-wei Xu (email [email protected])
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Publisher: Portland Press Ltd
Received:
August 20 2016
Revision Received:
September 26 2016
Accepted:
October 04 2016
Accepted Manuscript online:
October 04 2016
Online ISSN: 1470-8736
Print ISSN: 0143-5221
© 2016 The Author(s). published by Portland Press Limited on behalf of the Biochemical Society
2016
Clin Sci (Lond) (2017) 131 (2): 141–154.
Article history
Received:
August 20 2016
Revision Received:
September 26 2016
Accepted:
October 04 2016
Accepted Manuscript online:
October 04 2016
Connected Content
This is a commentary on:
DUSPs as critical regulators of cardiac hypertrophy
Citation
Wei-ming Li, Yi-fan Zhao, Guo-fu Zhu, Wen-hui Peng, Meng-yun Zhu, Xue-jing Yu, Wei Chen, Da-chun Xu, Ya-wei Xu; Dual specific phosphatase 12 ameliorates cardiac hypertrophy in response to pressure overload. Clin Sci (Lond) 1 January 2017; 131 (2): 141–154. doi: https://doi.org/10.1042/CS20160664
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