Abstract:
:Met, the tyrosine kinase receptor for hepatocyte growth factor (HGF), mainly activates prosurvival pathways, including protection from apoptosis. In this work, we investigated the cardioprotective mechanisms of Met activation by agonist monoclonal antibodies (mAbs). Cobalt chloride (CoCl2), a chemical mimetic of hypoxia, was used to induce cardiac damage in H9c2 cardiomyoblasts, which resulted in reduction of cell viability by (i) caspase-dependent apoptosis and (ii) - surprisingly - autophagy. Blocking either apoptosis with the caspase inhibitor benzyloxycarbonyl-VAD-fluoromethylketone or autophagosome formation with 3-methyladenine prevented loss of cell viability, which suggests that both processes contribute to cardiomyoblast injury. Concomitant treatment with Met-activating antibodies or HGF prevented apoptosis and autophagy. Pro-autophagic Redd1, Bnip3 and phospho-AMPK proteins, which are known to promote autophagy through inactivation of the mTOR pathway, were induced by CoCl2. Mechanistically, Met agonist antibodies or HGF prevented the inhibition of mTOR and reduced the flux of autophagosome formation. Accordingly, their anti-autophagic function was completely blunted by Temsirolimus, a specific mTOR inhibitor. Targeted Met activation was successful also in the setting of low oxygen conditions, in which Met agonist antibodies or HGF demonstrated anti-apoptotic and anti-autophagic effects. Activation of the Met pathway is thus a promising novel therapeutic tool for ischaemic injury.
journal_name
Cell Death Disjournal_title
Cell death & diseaseauthors
Gallo S,Gatti S,Sala V,Albano R,Costelli P,Casanova E,Comoglio PM,Crepaldi Tdoi
10.1038/cddis.2014.155subject
Has Abstractpub_date
2014-04-17 00:00:00pages
e1185issn
2041-4889pii
cddis2014155journal_volume
5pub_type
杂志文章abstract::Hippo signaling plays critical roles in intestinal regeneration. However, the mechanisms which regulate its activity in vivo are largely unknown. We hypothesize that protease-activated receptor 2 (PAR2) signaling, which could be activated by trypsin, might affect YAP activity in the setting of tissue damage and regene...
journal_title:Cell death & disease
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journal_title:Cell death & disease
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journal_title:Cell death & disease
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journal_title:Cell death & disease
pub_type: 杂志文章,评审
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journal_title:Cell death & disease
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journal_title:Cell death & disease
pub_type: 杂志文章
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journal_title:Cell death & disease
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journal_title:Cell death & disease
pub_type: 杂志文章,收录出版
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pub_type: 杂志文章
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pub_type: 杂志文章
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journal_title:Cell death & disease
pub_type: 已发布勘误
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journal_title:Cell death & disease
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journal_title:Cell death & disease
pub_type: 杂志文章
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journal_title:Cell death & disease
pub_type: 杂志文章
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更新日期:2017-06-08 00:00:00