Abrogation of ER stress-induced apoptosis of alveolar epithelial cells by angiotensin 1-7

Earlier work showed that apoptosis of alveolar epithelial cells (AECs) in response to endogenous or xenobiotic factors is regulated by autocrine generation of angiotensin (ANG) II and its counterregulatory peptide ANG1-7. Mutations in surfactant protein C (SP-C) induce endoplasmic reticulum (ER) str...

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Bibliographic Details
Published in:American journal of physiology. Lung cellular and molecular physiology 2013-07, Vol.305 (1), p.L33-L41
Main Authors: Uhal, Bruce D, Nguyen, Hang, Dang, MyTrang, Gopallawa, Indiwari, Jiang, Jing, Dang, Vinh, Ono, Shinji, Morimoto, Konosuke
Format: Article
Language:English
Subjects:
ACE inhibitors
Angiotensin I - pharmacology
Angiotensin II - pharmacology
Angiotensin Receptor Antagonists - pharmacology
Antihypertensive Agents - pharmacology
Antineoplastic Agents - pharmacology
Apoptosis
Apoptosis - drug effects
Autocrine Communication
Call for Papers
Cells
Cells, Cultured
Endoplasmic Reticulum Stress - drug effects
Epithelial Cells - drug effects
Epithelial Cells - pathology
Humans
Leupeptins - pharmacology
Lung diseases
Mutation
Peptide Fragments - pharmacology
Proteins
Pulmonary Alveoli - drug effects
Pulmonary Alveoli - pathology
Pulmonary Surfactant-Associated Protein C - antagonists & inhibitors
Pulmonary Surfactant-Associated Protein C - genetics
Pulmonary Surfactant-Associated Protein C - metabolism
Receptors, Angiotensin - chemistry
Signal Transduction - drug effects
Surfactants
Vasoconstrictor Agents - pharmacology
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Summary:Earlier work showed that apoptosis of alveolar epithelial cells (AECs) in response to endogenous or xenobiotic factors is regulated by autocrine generation of angiotensin (ANG) II and its counterregulatory peptide ANG1-7. Mutations in surfactant protein C (SP-C) induce endoplasmic reticulum (ER) stress and apoptosis in AECs and cause lung fibrosis. This study tested the hypothesis that ER stress-induced apoptosis of AECs might also be regulated by the autocrine ANGII/ANG1-7 system of AECs. ER stress was induced in A549 cells or primary cultures of human AECs with the proteasome inhibitor MG132 or the SP-C BRICHOS domain mutant G100S. ER stress activated the ANGII-generating enzyme cathepsin D and simultaneously decreased the ANGII-degrading enzyme ACE-2, which normally generates the antiapoptotic peptide ANG1-7. TAPI-2, an inhibitor of ADAM17/TACE, significantly reduced both the activation of cathepsin D and the loss of ACE-2. Apoptosis of AECs induced by ER stress was measured by assays of mitochondrial function, JNK activation, caspase activation, and nuclear fragmentation. Apoptosis induced by either MG132 or the SP-C BRICHOS mutant G100S was significantly inhibited by the ANG receptor blocker saralasin and was completely abrogated by ANG1-7. Inhibition by ANG1-7 was blocked by the specific mas antagonist A779. 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 ANG1-7. They also suggest that therapeutic strategies aimed at administering ANG1-7 or stimulating ACE-2 may hold potential for the management of ER stress-induced fibrotic lung disorders.
ISSN:1040-0605
1522-1504
DOI:10.1152/ajplung.00001.2013