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Endoplasmic reticulum stress induces alveolar epithelial cell apoptosis through the activation of the unfolded protein response (1010.10)
Author(s) -
Nguyen Hang,
Dang MyTrang,
Ono Shinji,
Morimoto Konosuke,
Uhal Bruce
Publication year - 2014
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.28.1_supplement.1010.10
Subject(s) - unfolded protein response , mg132 , apoptosis , endoplasmic reticulum , microbiology and biotechnology , chemistry , autocrine signalling , xbp1 , proteasome inhibitor , biology , biochemistry , receptor , rna , rna splicing , gene
STUDY OBJECTIVE: Our prior work showed that ER stress‐induced apoptosis of AECs is regulated by the autocrine angiotensin (ANG)II/ANG1‐7 system. MG132 or surfactant protein C (SP‐C) BRICHOS domain mutation G100S induced apoptosis in human AECs by activating cathepsin D or decreasing ACE‐2. This study tested the hypothesis that ER stress‐induced apoptosis of human AECs might be mediated by the activation of the UPR thus regulates the ANGII/ANG1‐7 system. METHODS: A549 cells were challenged with proteasome inhibitor MG132 or SP‐C BRICHOS domain mutant G100S. The level of UPR markers and angiotensin components were measured by Western blotting. AEC apoptosis was measured by caspase activation and nuclear fragmentation. RESULTS: MG132‐ or G100S mutation‐induced ER stress activated the UPR pathways (eIF2α, ATF4, IRE1, XBP1), which led to an increase of cathepsin D or a decrease of ACE‐2. These changes were inhibited by the presence of UPR inhibitors, thus blocking the AEC apoptosis caused by the ER stress. CONCLUSIONS : These data show that ER stress induces apoptosis in human AECs through UPR‐mediated pathways that in turn regulate the autocrine ANGII/ANG1‐7 system. It is also demonstrated that ER stress‐induced AEC apoptosis can be blocked by inhibition of the UPR pathways. Grant Funding Source : PHS HL‐45136