Glucagon-like Peptide 1 Can Directly Protect the Heart Against Ischemia/Reperfusion Injury

  1. Amal K. Bose1,
  2. Mihaela M. Mocanu1,
  3. Richard D. Carr2,
  4. Christian L. Brand2 and
  5. Derek M. Yellon1
  1. 1Hatter Institute and Centre for Cardiology, University College London Hospital and Medical School, London, U.K
  2. 2NovoNordisk, Bagsværd, Denmark
  1. Address correspondence and reprint requests to Professor Derek M. Yellon, The Hatter Institute for Cardiovascular Studies, University College London Hospital and Medical School, Grafton Way, London WC1E, U.K. E-mail: d.yellon{at}ucl.ac.uk

Abstract

Glucagon-like peptide 1 (GLP-1), a gut incretin hormone that stimulates insulin secretion, also activates antiapoptotic signaling pathways such as phosphoinositide 3-kinase and mitogen-activated protein kinase in pancreatic and insulinoma cells. Since these kinases have been shown to protect against myocardial injury, we hypothesized that GLP-1 could directly protect the heart against such injury via these prosurvival signaling pathways. Both isolated perfused rat heart and whole animal models of ischemia/reperfusion were used, with infarct size measured as the end point of injury. In both studies, GLP-1 added before ischemia demonstrated a significant reduction in infarction compared with the valine pyrrolidide (an inhibitor of its breakdown) or saline groups. This protection was abolished in the in vitro hearts by the GLP-1 receptor antagonist exendin (9-39), the cAMP inhibitor Rp-cAMP, the PI3kinase inhibitor LY294002, and the p42/44 mitogen-activated protein kinase inhibitor UO126. Western blot analysis demonstrated the phosphorylation of the proapoptotic peptide BAD in the GLP-1–treated groups. We show for the first time that GLP-1 protects against myocardial infarction in the isolated and intact rat heart. This protection appears to involve activating multiple prosurvival kinases. This finding may represent a new therapeutic potential for this class of drug currently undergoing clinical trials in the treatment of type 2 diabetes.

Footnotes

  • D.M.Y. has received grant/research support from NovoNordisk, Denmark.

    • Accepted September 10, 2004.
    • Received July 6, 2004.
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