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PMID:24743740

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Citation

Gallo, S, Gatti, S, Sala, V, Albano, R, Costelli, P, Casanova, E, Comoglio, PM and Crepaldi, T (2014) Agonist antibodies activating the Met receptor protect cardiomyoblasts from cobalt chloride-induced apoptosis and autophagy. Cell Death Dis 5:e1185

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.

Links

PubMed PMC4001309 Online version:10.1038/cddis.2014.155

Keywords

Animals; Antibodies, Monoclonal/pharmacology; Apoptosis/drug effects; Autophagy/drug effects; Cardiotonic Agents/pharmacology; Cell Line; Cobalt; Cytoprotection/drug effects; Hepatocyte Growth Factor/pharmacology; Myocytes, Cardiac/drug effects; Myocytes, Cardiac/pathology; Phosphorylation/drug effects; Proto-Oncogene Proteins c-met/agonists; Proto-Oncogene Proteins c-met/metabolism; Rats; Signal Transduction/drug effects; TOR Serine-Threonine Kinases/metabolism

Significance

Annotations

Gene product Qualifier GO Term Evidence Code with/from Aspect Extension Notes Status

HUMAN:MET

involved_in

GO:0010507: negative regulation of autophagy

ECO:0000303: author statement without traceable support used in manual assertion

P

  • occurs_in:(CL:0010021)

Seeded From UniProt

complete

HUMAN:HGF

involved_in

GO:0010507: negative regulation of autophagy

ECO:0000303: author statement without traceable support used in manual assertion

P

  • occurs_in:(CL:0010021)

Seeded From UniProt

complete

HUMAN:HGF

involved_in

GO:0010507: negative regulation of autophagy

ECO:0000303: author statement without traceable support used in manual assertion

P

occurs_in:(CL:0010021)

Seeded From UniProt

complete

HUMAN:MET

involved_in

GO:0010507: negative regulation of autophagy

ECO:0000303: author statement without traceable support used in manual assertion

P

occurs_in:(CL:0010021)

Seeded From UniProt

complete

Notes

See also

References

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