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

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Listed:
  • Yufeng Yao

    (Huazhong University of Science and Technology)

  • Qiulun Lu

    (Huazhong University of Science and Technology)

  • Zhenkun Hu

    (Huazhong University of Science and Technology)

  • Yubin Yu

    (Huazhong University of Science and Technology)

  • Qiuyun Chen

    (Cleveland Clinic
    CCLCM, Case Western Reserve University
    Case Western Reserve University)

  • Qing K. Wang

    (Huazhong University of Science and Technology
    Cleveland Clinic
    CCLCM, Case Western Reserve University
    Case Western Reserve University)

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.

Suggested Citation

  • Yufeng Yao & Qiulun Lu & Zhenkun Hu & Yubin Yu & Qiuyun Chen & Qing K. Wang, 2017. "A non-canonical pathway regulates ER stress signaling and blocks ER stress-induced apoptosis and heart failure," Nature Communications, Nature, vol. 8(1), pages 1-15, December.
    • Handle: RePEc:nat:natcom:v:8:y:2017:i:1:d:10.1038_s41467-017-00171-w
    DOI: 10.1038/s41467-017-00171-w
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    Cited by:

    1. Xingwen Da & Ziyan Li & Xiaofan Huang & Zuhan He & Yubing Yu & Tongtong Tian & Chengqi Xu & Yufeng Yao & Qing K. Wang, 2023. "AGGF1 therapy inhibits thoracic aortic aneurysms by enhancing integrin α7-mediated inhibition of TGF-β1 maturation and ERK1/2 signaling," Nature Communications, Nature, vol. 14(1), pages 1-19, December.

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