Premium
Apelin‐induced cardioprotection against ischaemia/reperfusion injury: roles of epidermal growth factor and Src
Author(s) -
Folino A.,
Accomasso L.,
Giachino C.,
Montarolo P. G.,
Losano G.,
Pagliaro P.,
Rastaldo R.
Publication year - 2018
Publication title -
acta physiologica
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.591
H-Index - 116
eISSN - 1748-1716
pISSN - 1748-1708
DOI - 10.1111/apha.12924
Subject(s) - apelin , cardioprotection , transactivation , protein kinase b , proto oncogene tyrosine protein kinase src , pten , pi3k/akt/mtor pathway , phosphorylation , reperfusion injury , medicine , epidermal growth factor receptor , pharmacology , endocrinology , chemistry , ischemia , microbiology and biotechnology , signal transduction , receptor , biology , biochemistry , transcription factor , gene
Aim Apelin, the ligand of the G‐protein‐coupled receptor (GPCR) APJ, exerts a post‐conditioning‐like protection against ischaemia/reperfusion injury through activation of PI3K‐Akt‐NO signalling. The pathway connecting APJ to PI3K is still unknown. As other GPCR ligands act through transactivation of epidermal growth factor receptor (EGFR) via a matrix metalloproteinase (MMP) or Src kinase, we investigated whether EGFR transactivation is involved in the following three features of apelin‐induced cardioprotection: limitation of infarct size, suppression of contracture and improvement of post‐ischaemic contractile recovery. Method Isolated rat hearts underwent 30 min of global ischaemia and 2 h of reperfusion. Apelin (0.5 μ m ) was infused during the first 20 min of reperfusion. EGFR, MMP or Src was inhibited to study the pathway connecting APJ to PI3K. Key components of RISK pathway, namely PI3K, guanylyl cyclase or mitochondrial K + ‐ATP channels, were also inhibited. Apelin‐induced EGFR and phosphatase and tensing homolog (PTEN) phosphorylation were assessed. Left ventricular pressure and infarct size were measured. Results Apelin‐induced reductions in infarct size and myocardial contracture were prevented by the inhibition of EGFR, Src, MMP or RISK pathway. The involvement of EGFR was confirmed by its phosphorylation. However, neither direct EGFR nor MMP inhibition affected apelin‐induced improvement of early post‐ischaemic contractile recovery, which was suppressed by Src and RISK inhibitors only. Apelin also increased PTEN phosphorylation, which was removed by Src inhibition. Conclusion While EGFR and MMP limit infarct size and contracture, Src or RISK pathway inhibition suppresses the three features of cardioprotection. Src does not only transactivate EGFR, but also inhibits PTEN by phosphorylation thus playing a crucial role in apelin‐induced cardioprotection.