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Nat Commun. 2017 Jul 25;8(1):133. doi: 10.1038/s41467-017-00171-w.

A non-canonical pathway regulates ER stress signaling and blocks ER stress-induced apoptosis and heart failure.

Yao Y1, Lu Q1, Hu Z1, Yu Y1, Chen Q2,3,4, Wang QK5,6,7,8.

Author information

1
Key Laboratory of Molecular Biophysics of the Ministry of Education, College of Life Science and Technology and Center for Human Genome Research, Huazhong University of Science and Technology, Wuhan, Hubei Province, 430074, China.
2
Department of Molecular Cardiology, Center for Cardiovascular Genetics, Cleveland Clinic, Cleveland, OH, 44195, USA.
3
Department of Molecular Medicine, CCLCM, Case Western Reserve University, Cleveland, OH, 44195, USA.
4
Department of Genetics and Genome Sciences, Case Western Reserve University, Cleveland, OH, 44195, USA.
5
Key Laboratory of Molecular Biophysics of the Ministry of Education, College of Life Science and Technology and Center for Human Genome Research, Huazhong University of Science and Technology, Wuhan, Hubei Province, 430074, China. qkwang@hust.edu.cn.
6
Department of Molecular Cardiology, Center for Cardiovascular Genetics, Cleveland Clinic, Cleveland, OH, 44195, USA. qkwang@hust.edu.cn.
7
Department of Molecular Medicine, CCLCM, Case Western Reserve University, Cleveland, OH, 44195, USA. qkwang@hust.edu.cn.
8
Department of Genetics and Genome Sciences, Case Western Reserve University, Cleveland, OH, 44195, USA. qkwang@hust.edu.cn.

Abstract

Endoplasmic reticulum stress is an evolutionarily conserved cell stress response associated with numerous diseases, including cardiac hypertrophy and heart failure. The major endoplasmic reticulum stress signaling pathway causing cardiac hypertrophy involves endoplasmic reticulum stress sensor PERK (protein kinase-like kinase) and eIF2α-ATF4-CHOP signaling. Here, we describe a non-canonical, AGGF1-mediated regulatory system for endoplasmic reticulum stress signaling associated with increased p-eIF2α and ATF4 and decreased sXBP1 and CHOP. Specifically, we see a reduced AGGF1 level consistently associated with induction of endoplasmic reticulum stress signaling in mouse models and human patients with heart failure. Mechanistically, AGGF1 regulates endoplasmic reticulum stress signaling by inhibiting ERK1/2 activation, which reduces the level of transcriptional repressor ZEB1, leading to induced expression of miR-183-5p. miR-183-5p post-transcriptionally downregulates CHOP and inhibits endoplasmic reticulum stress-induced apoptosis. AGGF1 protein therapy and miR-183-5p regulate endoplasmic reticulum stress signaling and block endoplasmic reticulum stress-induced apoptosis, cardiac hypertrophy, and heart failure, providing an attractive paradigm for treatment of cardiac hypertrophy and heart failure.Endoplasmic reticulum (ER) stress promotes cardiac dysfunction. Here the authors uncover a pathway whereby AGGF1 blocks ER stress by inhibiting ERK1/2 activation and the transcriptional repressor ZEB1, leading to induction of miR-183-5p and down-regulation of CHOP, and show that AGGF1 can effectively treat cardiac hypertrophy and heart failure.

PMID:
28743963
PMCID:
PMC5527107
DOI:
10.1038/s41467-017-00171-w
[Indexed for MEDLINE]
Free PMC Article

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