Abstract 147: Glucagon-like Peptide-1 Receptor Activation Reverses Cardiac Mitochondrial Remodeling In Advanced Type 2 Diabetes Via Suppression Of Nox4.
PURPOSE: Damaged cardiac mitochondria are one of the critical features of diabetic cardiomyopathy. We indeed demonstrated that diet-induced type 2 diabetes mellitus (T2DM) exhibited cardiac mitochondria remodeling, which were reversed by glucagon-like peptide-1 receptor (GLP-1R) agonist exendin-4 (Ex4) (submitted as another abstract to BCVS 2013); however, it remains unclear whether the mitochondrial remodeling induced by diabetes may be reversible even at an advanced disease stage and Ex4 may be strong enough to exhibit the cardioprotective effects on such a progressive T2DM.
Methods and Results: Genetic T2DM model (KKAy mice of which casual blood glucose levels is more than 30 mmol/L) were allocated into exendin-4 (Ex4, 24 nmole/kg/day for 40 days; KK-Ex4) and vehicle groups (KK-v). In KK-v, their systolic left-ventricular (LV) function was normal range, whereas they exhibited diastolic LV dysfunction and myocardial hypertrophy, which were ameliorated by Ex4. Myocardial fibrosis and cardiac steatosis (detected by Oil-red-O-staining and anti-ceramide antibody) were reduced in KK-ex4. Transmission electron microscopy revealed that Ex-4 normalized cardiac mitochondrial remodeling in terms of morphology, size, and number observed in KK-v. Ex4 attenuated mitochondrial damage which was detected by its specific dye mitotracker-red and alternatively monitored by mitofusin (Mfn)1/Mfn2 ratio. DHE staining revealed that Ex-4 reduced cardiac oxidative stress observed in KK-v. Ex4 modulated cardiac oxidative stress balance by reduction of NOX4 level; whereas it had no influence on NOX2 level and antioxidative molecules (SOD, thioredoxin, glutathione peroxidase), contrarily to those cases observed in diet-induced T2DM heart.
Conclusions: Mitochondrial remodeling induced by T2DM was found to be reversible even at an advanced disease stage and Ex4 was strong enough to exhibit the cardioprotective effects on such a progressive T2DM by attenuating cardiac oxidative stress, at least in part, by suppression of NOX4.
- © 2013 by American Heart Association, Inc.