Dual specific phosphatase 12 ameliorates cardiac hypertrophy in response to pressure overload

被引:17
|
作者
Li, Wei-ming [1 ]
Zhao, Yi-fan [1 ]
Zhu, Guo-fu [1 ]
Peng, Wen-hui [1 ]
Zhu, Meng-yun [1 ]
Yu, Xue-jing [1 ]
Chen, Wei [1 ]
Xu, Da-chun [1 ]
Xu, Ya-wei [1 ]
机构
[1] Tongji Univ, Shanghai Peoples Hosp 10, Dept Cardiol, Sch Med, Shanghai 200072, Peoples R China
基金
中国国家自然科学基金;
关键词
cardiac hypertrophy; dual specific phosphatase 12; c-Jun N-terminal kinase (JNK); signalling pathway; SP600125; N-TERMINAL KINASE; HEART-FAILURE; ACTIVATION; REGULATORS; CARDIOMYOPATHY; IDENTIFICATION; APOPTOSIS; REVEALS; BINDING; ERK1/2;
D O I
10.1042/CS20160664
中图分类号
R-3 [医学研究方法]; R3 [基础医学];
学科分类号
1001 ;
摘要
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.
引用
收藏
页码:141 / 154
页数:14
相关论文
共 50 条
  • [11] Thymoquinone ameliorates pressure overload-induced cardiac hypertrophy by activating the AMPK signalling pathway
    Chen, Heng
    Zhuo, Chengui
    Zu, Aohan
    Yuan, Shuai
    Zhang, Han
    Zhao, Jianqiang
    Zheng, Liangrong
    JOURNAL OF CELLULAR AND MOLECULAR MEDICINE, 2022, 26 (03) : 855 - 867
  • [12] Hawthorn alters remodeling and ameliorates LV dysfunction in pressure overload-induced cardiac hypertrophy
    Hwang, Hyun Seok
    Ghannam, Michael M. J.
    Boluyt, Marvin O.
    Converso, Kimber
    Russell, Mark W.
    Bleske, Barry E.
    FASEB JOURNAL, 2007, 21 (06): : A1260 - A1260
  • [13] PATHOLOGY OF CARDIAC-HYPERTROPHY IN PRESSURE OVERLOAD
    TEZUKA, F
    TAKAHASHI, T
    JAPANESE CIRCULATION JOURNAL-ENGLISH EDITION, 1976, 40 (10): : 1111 - 1118
  • [14] Calcineurin regulation in pressure overload cardiac hypertrophy
    Li, J
    Guo, HY
    Takagi, G
    Hong, C
    Karoor, V
    West, M
    CLINICAL AND EXPERIMENTAL PHARMACOLOGY AND PHYSIOLOGY, 2003, 30 (07) : A40 - A41
  • [15] Microtubule stabilization in pressure overload cardiac hypertrophy
    Sato, H
    Nagai, T
    Kuppuswamy, D
    Narishige, T
    Koide, M
    Menick, DR
    Cooper, G
    JOURNAL OF CELL BIOLOGY, 1997, 139 (04): : 963 - 973
  • [16] Nifedipine Inhibits Cardiac Hypertrophy and Left Ventricular Dysfunction in Response to Pressure Overload
    Ago, Tetsuro
    Yang, Yanfei
    Zhai, Peiyong
    Sadoshima, Junichi
    JOURNAL OF CARDIOVASCULAR TRANSLATIONAL RESEARCH, 2010, 3 (04) : 304 - 313
  • [17] CCDC11 Promotes Cardiac Hypertrophy and Dysfunction in Response to Pressure Overload
    Chen, Jiawei
    Li, Chang
    Wang, Xiaoqun
    JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY, 2018, 72 (16) : C62 - C62
  • [18] ACE gene confers increased cardiac hypertrophy response to pressure overload in mice
    Silva, G
    Silva, GJJ
    Moreira, ED
    Krieger, EM
    Krieger, JE
    JOURNAL OF HYPERTENSION, 2004, 22 : S8 - S8
  • [19] Nifedipine Inhibits Cardiac Hypertrophy and Left Ventricular Dysfunction in Response to Pressure Overload
    Tetsuro Ago
    Yanfei Yang
    Peiyong Zhai
    Junichi Sadoshima
    Journal of Cardiovascular Translational Research, 2010, 3 : 304 - 313
  • [20] c-Flip overexpression reduces cardiac hypertrophy in response to pressure overload
    Giampietri, Claudia
    Petrungaro, Simonetta
    Musumeci, Marco
    Coluccia, Pierpaolo
    Antonangeli, Fabrizio
    De Cesaris, Paola
    Filippini, Antonio
    Marano, Giuseppe
    Ziparo, Elio
    JOURNAL OF HYPERTENSION, 2008, 26 (05) : 1008 - 1016