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

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

Glucagon‐like Peptide‐1 and Myocardial Protection: More than Glycemic Control

“…Furthermore, cellular studies suggest that GLP-1 may activate cardioprotective and pro-survival pathways contributing to its beneficial effects. 15,16 More basic investigation and clinical studies are needed to confirm and advance this potentially important therapeutic approach.…”

“…Other laboratories have demonstrated similar salutary effects of GLP-1 in rodent models of myocardial infarction. Bose et al 16 showed that GLP-1 treatment reduced infarct size compared to control both In Vitro (26.7 ± 2.7% vs 58.7 ± 4.1%) and in vivo (20.0 ± 2.8% vs 44.3 ± 2.4%) in rat models of permanent coronary artery occlusion (35 minutes of ischemia followed by 120 minutes reperfusion). Taken together, these data suggest that GLP-1 has direct effects on post-ischemic myocardium, and the effects are mediated through the myocardial GLP-1 receptor.…”

Rationale and design of the EXenatide Study of Cardiovascular Event Lowering (EXSCEL) trial

“…29 Studies in animal models suggest beneficial effects of GLP-1 on atherogenesis, by inhibiting the inflammatory response in macrophages and endothelial adhesion 30 and modulating endothelial function. 31,32 Further cardioprotective effects, by means of increased coronary flow, 29 reduced myocardial infarct size, 33 and improved left ventricular function, have also been suggested by animal data. 30,34 Human mechanistic studies are consistent with these findings demonstrating an improvement in flow-mediated vasodilation in the postprandial state, 13 reduced infarct size in patients with ST-segment elevation myocardial infarction, 12,14 and an improvement in left ventricular ejection fraction in patients with heart failure.…”

“…24,33 In contrast to rodents, GLP-1 receptor expression on primate thyroid C-cells is very low, and no changes have been observed with in vitro stimulation of human C-cells by GLP-1 receptor agonists. 10,24 Patients with a personal or family history of medullary thyroid cancer or Multiple Endocrine Neoplasia type 2 (MEN2) will be excluded from ESXCEL.…”

A new era in the management of type 2 diabetes: Is cardioprotection at long last a reality?

“…Research has manipulated the biology of the entero-insular axis producing both injectable GLP-1 agonists that are used as an exogenous source of GLP-1 and oral DPP-4 inhibitors that shield the endogenous peptide from degradation [3]. Findings from our laboratory demonstrated for the first time that the administration of either GLP-1 native peptide or the DPP-4 inhibitor protects against myocardial IRI in the isolated rat heart model through a mechanism not driven by the stimulation of insulin secretion, but by the activation of intracellular prosurvival kinases cascades [4]. Subsequently, Lonborg et al showed that the infusion of exenatide, a GLP-1analogue, prior to primary percutaneous coronary intervention reduces myocardial infarct size patients presenting with ST-segment elevation myocardial infarction [5].…”