Open AccessCardiac‐specific Mst1 deficiency inhibits ROS ‐mediated JNK signalling to alleviate Ang II ‐induced cardiomyocyte apoptosis
Author(s) -
Cheng Zheng,
Zhang Mingming,
Hu Jianqiang,
Lin Jie,
Feng Xinyu,
Wang Shanjie,
Wang Tingting,
Gao Erhe,
Wang Haichang,
Sun Dongdong
Publication year - 2019
Publication title -
journal of cellular and molecular medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.44
H-Index - 130
eISSN - 1582-4934
pISSN - 1582-1838
DOI - 10.1111/jcmm.13958
Subject(s) - apoptosis , kinase , angiotensin ii , signal transduction , microbiology and biotechnology , reactive oxygen species , p38 mitogen activated protein kinases , phosphorylation , knockout mouse , chemistry , biology , mapk/erk pathway , biochemistry , receptor
Apoptosis is associated with various myocardial diseases. Angiotensin II (Ang II ) plays a central role in the pathogenesis of RAAS ‐triggered cardiac apoptosis. Our previous studies showed that mammalian Ste20‐like kinase 1 (Mst1) aggravates cardiac dysfunction in cardiomyocyte under pathological conditions, but its role in Ang II ‐mediated cardiomyocyte apoptosis is not known. We addressed this in the present study by investigating whether cardiac‐specific Mst1 knockout can alleviate Ang II ‐induced cardiomyocyte apoptosis along with the underlying mechanisms. In vitro and in vivo experiments showed that Ang II increased intracellular reactive oxygen species ( ROS ) production and cardiomyocyte apoptosis; these were reversed by administration of the ROS scavenger N‐acetylcysteine and by Mst1 deficiency, which suppressed c‐Jun N‐terminal kinase ( JNK ) phosphorylation and downstream signaling. Interestingly, Mst1 knockout failed to alleviate Ang II ‐induced phosphorylation of extracellular signal‐regulated kinase 1/2, and inactivated apoptosis signal‐regulating kinase1 ( ASK 1) by promoting its association with thioredoxin (Trx), which reversed the Ang II ‐induced activation of the ASK 1– JNK pathway and suppressed Ang II ‐induced cardiomyocyte apoptosis. Thus, cardiac‐specific Mst1 knockout inhibits ROS ‐mediated JNK signalling to block Ang II ‐induced cardiomyocyte apoptosis, suggesting Mst1 as a potential therapeutic target for treatment of RAAS ‐activated heart failure.