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Endothelial apoptosis promotes lung tissue remodeling via activation of matrix metalloprotease
Author(s) -
Yin Jun,
Wang Liming,
Pasqualini Renata,
Tuder Rubin M.,
Kuebler Wolfgang M.
Publication year - 2011
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.25.1_supplement.300.5
Subject(s) - matrix metalloproteinase , apoptosis , microbiology and biotechnology , annexin , reactive oxygen species , caspase , chemistry , annexin a5 , endothelial stem cell , programmed cell death , biology , cancer research , biochemistry , in vitro
Endothelial apoptosis has been implicated in abnormal lung tissue remodeling. Here, we tested the hypothesis that lung endothelial apoptosis, via formation of reactive oxygen species (ROS), may trigger matrix metalloprotease (MMP) activation, which in turn propagates lung disease by promoting further apoptosis and tissue remodeling. In isolated perfused mouse lungs, programmed endothelial cell death was induced by a pro‐apoptotic peptide and verified by real‐time imaging of annexin‐V, mitochondrial depolarization and the FLICA ™ assay for caspase activation. Endothelial apoptosis was associated with enhanced ROS formation, as shown by imaging of H 2 DCF‐loaded cells, and increased pericellular MMP activity, as demonstrated by imaging of DQ‐gelatin which becomes unquenched upon cleavage by MMPs. Inhibition of apoptosis by the caspase inhibitor Z‐Asp‐CH 2 ‐DCB attenuated MMP activation. Conversely, the MMP inhibitor GM6001 and the ROS scavenger N ‐acetyl‐l‐cysteine each attenuated endothelial apoptosis. Our data suggest an intricate interplay between endothelial apoptosis and MMP activation that is regulated by ROS. The evolving positive feedback may critically promote lung tissue remodeling. Grant Funding Source : Canadian Institutes of Health Research (CIHR), Heart and Stroke Foundation of Canada (HSFC), German Research Foundation (DFG)