Myocardial ischaemia-reperfusion injury is attenuated by intact glucagon like peptide-1 (GLP-1) in the in vitro rat heart and may involve the p70s6K pathway.
METHODS
Glucagon Like Peptide-1 (GLP-1), one of the most potent incretin hormones, has potential beneficial actions on the ischaemic and failing heart. This study sought to further identify the mechanisms of action of GLP-1 on the ischaemic heart using an in vitro isolated perfused rat heart model of ischaemic-reperfusion injury (measuring infarct size to area of risk (%)) subjected to 35 min regional ischaemia and 2 h reperfusion. To examine the effect of intact GLP-1 we used an inhibitor of GLP-1 breakdown, Valine pyrrolidide (VP). The downstream target of phosphatidylinositol 3-kinase includes the mTOR/p70s6 kinase pathway which was pharmacologically inhibited by rapamycin.


CONCLUSIONS
GLP-1 alone did not decrease myocardial infarction (54.4 +/- 3.1%). VP alone did not decrease myocardial infarction (52.5 +/- 4%). GLP-1 in the presence of VP produced significant reduction in myocardial infarction compared to control hearts (28.4 +/- 2.7% vs. 56.4 +/- 3.9% vs. P < 0.05). Inhibiting p70s6 Kinase with rapamycin completely abolished GLP-1 induced protection (57.1 +/- 4.9% vs. 28.4 +/- 2.7% P < 0.05). There was no detectable increase in the phosphorylated p70s6k after either 5 or 10 min of treatment with GLP-1/VP or with VP alone in comparison to control blots. In conclusion we show for the first time that the protective effects of GLP-1 are mediated by intact GLP-1 and can be inhibited by blocking the p70s6 kinase.
Bose
Amal K
AK
The Hatter Institute and Centre for Cardiology, University College London Hospital & Medical School, Grafton Way, London, WC1E, UK. amal@doctors.net.uk
Mocanu
Mihaela M
MM
Carr
Richard D
RD
Yellon
Derek M
DM
D000818:Animals; D015153:Blotting, Western; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000494:pharmacology; D052216:Glucagon-Like Peptide 1 / Q000494:pharmacology*; D066298:In Vitro Techniques; D054795:Incretins / Q000494:pharmacology*; D008297:Male; D009203:Myocardial Infarction / Q000188:drug therapy*; D015428:Myocardial Reperfusion Injury / Q000188:drug therapy* / Q000503:physiopathology; D019869:Phosphatidylinositol 3-Kinases / Q000187:drug effects / Q000378:metabolism; D011494:Protein Kinases / Q000187:drug effects / Q000378:metabolism; D011758:Pyrroles / Q000494:pharmacology; D011897:Random Allocation; D051381:Rats; D017207:Rats, Sprague-Dawley; D038762:Ribosomal Protein S6 Kinases, 70-kDa / Q000187:drug effects* / Q000378:metabolism; D015398:Signal Transduction; D020123:Sirolimus / Q000494:pharmacology; D058570:TOR Serine-Threonine Kinases; D013997:Time Factors; D014633:Valine / Q000494:pharmacology
D004791:Enzyme Inhibitors; D052216:Glucagon-Like Peptide 1; D054795:Incretins; D019869:Phosphatidylinositol 3-Kinases; D011494:Protein Kinases; D011758:Pyrroles; D038762:Ribosomal Protein S6 Kinases, 70-kDa; D020123:Sirolimus; D058570:TOR Serine-Threonine Kinases; D014633:Valine; C112092:valine-pyrrolidide; C546845:mTOR protein, rat