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 |
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Authors: | Amal K Bose Mihaela M Mocanu Richard D Carr Derek M Yellon |
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Institution: | (1) The Hatter Institute and Centre for Cardiology, University College London Hospital & Medical School, Grafton Way, London, WC1E, UK;(2) NovoNordisk A/S, Novo Allé, 2880 Bagsvaerd, Denmark |
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Abstract: | Background and 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.
Results and conclusion 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. |
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Keywords: | glucagon like peptide-1 ischaemic preconditioning rapamycin reperfusion injury |
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