Premium
Induction of Apoptosis by ER Stress in Lung Alveolar Epithelial Cells (AECs) Is Blocked by Angiotensin 1–7 Through Mas
Author(s) -
Uhal Bruce,
Nguyen Hang,
Dang MyTrang,
Gopallawi Indiwari,
Dang Vinh,
Ono Shinji,
Morimoto Konosuke
Publication year - 2013
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.27.1_supplement.lb883
Subject(s) - mg132 , autocrine signalling , apoptosis , unfolded protein response , chemistry , angiotensin ii , angiotensin receptor , microbiology and biotechnology , a549 cell , cancer research , receptor , biology , biochemistry , proteasome inhibitor
STUDY OBJECTIVE Our prior work showed that apoptosis of AECs is regulated by autocrine generation of angiotensin (ANG) II and the counterregulatory ANG1–7. Mutations in surfactant protein C (SP‐C) induce endoplasmic reticulum (ER) stress and apoptosis. This study tested the hypothesis that ER stress‐induced apoptosis of AECs might also be regulated by autocrine ANGII/ANG1–7. METHODS A549 cells or primary cultures of human AECs were challenged with MG132 or the SP‐C BRICHOS domain mutant G100S. The ANGII‐generating and –degrading enzymes cathepsin D and ACE‐2 were measured by enzyme assay and western blot. Apoptosis was measured by mitochondrial function, JNK and caspase activation and nuclear fragmentation. RESULTS ER stress activated cathepsin D and decreased ACE‐2. Both changes were inhibited by TAPI‐2, a blocker of ADAM17/TACE. Apoptosis of A549 or primary human AECs induced by MG132 or the SP‐C BRICHOS mutant G100S was significantly inhibited by the nonselective ANG receptor blocker saralasin and was completely abrogated by ANG1–7 (both p<0.01). Inhibition by ANG1–7 was blocked by the specific mas antagonist A779. CONCLUSIONS These data show that ER stress‐induced apoptosis is mediated by the autocrine ANGII/ANG1–7 system in human AECs and demonstrate effective blockade of SP‐C mutation‐induced apoptosis by angiotensin1–7 through a mas‐ dependent mechanism. Support: PHS HL‐45136