Apelin-induced cardioprotection against ischaemia/reperfusion injury: roles of epidermal growth factor and Src
| Autor: | Pasquale Pagliaro, Raffaella Rastaldo, Lisa Accomasso, Anna Folino, Gianni Losano, Claudia Giachino, Pier Giorgio Montarolo |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
Male Transcriptional Activation medicine.medical_specialty Cardiotonic Agents Physiology contracture Myocardial Reperfusion Injury 030204 cardiovascular system & hematology contractility 03 medical and health sciences Transactivation 0302 clinical medicine Epidermal growth factor Internal medicine medicine PTEN Animals Rats Wistar PI3K/AKT/mTOR pathway Cardioprotection biology Epidermal Growth Factor Chemistry PTEN Phosphohydrolase Apelin Rats contractility contracture epidermal growth factor receptortransactivation infa rct size metalloproteinase reperfusion injury salvagekinases pathway 030104 developmental biology Endocrinology src-Family Kinases Cancer research biology.protein Phosphorylation epidermal growth factor receptortransactivation infa rct size metalloproteinase Proto-oncogene tyrosine-protein kinase Src Signal Transduction reperfusion injury salvagekinases pathway |
| Popis: | 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 μm) 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. |
| Databáze: | OpenAIRE |
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