Abstract 16521: Activation of the Glucagon-Like Peptide-1 Receptor Restores Myocardial Autophagic Flux and Reduces Mortality After Myocardial Infarction in Diabetic Rats
Background: The mechanism by which diabetes increases the mortality after myocardial infarction (MI) remains unclear. Here we examined the hypothesis that impaired autophagy is involved in aggravation of post-MI heart failure by type 2 diabetes (T2D), which is treatable with a glucagon-like peptide-1 (GLP-1) receptor analogue.
Methods and Results: Body weight and fasting plasma glucose (FPG: 288±41 vs. 136±7 mg/dl) were significantly higher in OLETF, a rat model of obese T2D, than in LETO, a non-diabetic control (both 25-30 weeks of age). Though left ventricular end-diastolic elastance was modestly higher in OLETF, end-systolic elastance was comparable between OLETF and LETO. Treatment with exenatide (Exe: 10 μg/kg/day), a GLP-1 receptor agonist, for 2 weeks did not affect FPG (316±20) in OLETF. At baseline, levels of phospho-Akt, -mTOR and -p70S6 kinase in the myocardium were lower and phospho-AMP kinase was higher in OLETF than in LETO, indicating pro-autophagic signaling in OLETF. LC3-II level was higher in OLETF than in LETO, though p62 protein levels were comparable. mRNA levels of LAMP2, Rab7, and cathepsins were similar in LETO and OLETF. At 12 hrs after MI by ligation of the left coronary artery, LC3-II protein in the non-infarcted remote myocardium increased similarly in LETO and OLETF. However, accumulation of p62 in the remote region was rather enhanced in OLETF, indicating disruption of autophagic clearance. Exe increased LC3-II level and reduced p62 protein after MI in OLETF, indicating restoration of autophagic flux. Mortality at 48 hrs after MI was higher in OLETF than in LETO (67% vs. 22%) and Exe treatment reduced the mortality (41%), although infarct size was comparable among treatment groups.
Conclusion: The findings suggest that impaired autophagic clearance in non-infarcted myocardium contributes to enhanced heart failure after MI in obese T2D. GLP-1 receptor activation reduces the post-MI mortality presumably by restoration of autophagic processes in the non-infarcted region of the heart.
- © 2013 by American Heart Association, Inc.