Glucagon-like peptide 1 can directly protect the heart against ischemia/reperfusion injury.
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.
Bose
Amal K
AK
The Hatter Institute for Cardiovascular Studies, University College London Hospital and Medical School, Grafton Way, London WC1E, UK.
Mocanu
Mihaela M
MM
Carr
Richard D
RD
Brand
Christian L
CL
Yellon
Derek M
DM
D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D002070:Butadienes / Q000494:pharmacology; D002867:Chromones / Q000494:pharmacology; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005934:Glucagon / Q000627:therapeutic use*; D052216:Glucagon-Like Peptide 1; D006339:Heart Rate / Q000187:drug effects; D066298:In Vitro Techniques; D007328:Insulin / Q000378:metabolism; D000078790:Insulin Secretion; D020935:MAP Kinase Signaling System / Q000187:drug effects / Q000502:physiology; D008297:Male; D009025:Morpholines / Q000494:pharmacology; D009203:Myocardial Infarction / Q000473:pathology / Q000517:prevention & control; D015428:Myocardial Reperfusion Injury / Q000517:prevention & control*; D009570:Nitriles / Q000494:pharmacology; D010446:Peptide Fragments / Q000627:therapeutic use*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011498:Protein Precursors / Q000627:therapeutic use*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013997:Time Factors
D002070:Butadienes; D002867:Chromones; D004791:Enzyme Inhibitors; D007328:Insulin; D009025:Morpholines; D009570:Nitriles; D010446:Peptide Fragments; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011498:Protein Precursors; C113580:U 0126; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; D052216:Glucagon-Like Peptide 1; D005934:Glucagon