Abstract 12374: Metformin Treatment in Metabolic Syndrome Inhibits Autophagy in Ischemic Myocardium
Background: Autophagy is a cellular process in which macromolecules and organelles are targeted and degraded. Autophagy is initiated in response to stresses such as starvation or hypoxia, and is essential for cell survival. More recently, autophagy is of increasing interest for its beneficial role in cardioprotection in ischemic cardiac injury. We developed a clinically relevant animal model of metabolic syndrome and chronic myocardial ischemia to investigate the effects of metformin, a commonly prescribed anti-hyperglycemic medication, on autophagy in the heart.
Methods: Ossabaw pigs were fed either a regular diet (OC, n=8), or a hypercaloric, high-fat/cholesterol diet (OHC, n=16) to induce metabolic syndrome. After three weeks, all animals underwent placement of an ameroid constrictor to the left circumflex coronary artery to induce chronic myocardial ischemia. OHC animals were split to hypercaloric diet alone (OHC, n=8) or hypercaloric diet supplemented with 500mg metformin twice daily (OHCM, n=8). After seven weeks of ameroid placement, the animals were sacrificed and the chronically ischemic myocardium was harvested for protein expression analysis.
Results: Markers of autophagy including LAMP1, LC3A, and LC3B were all down regulated in both the OHC and OHCM animals compared to the control. There was no difference in expression of inhibitors of the autophagy pathway including: MTOR, pMTOR, P70S6K, pP70S6K in the OHC and OHCM animals compared to control. See table.
CONCLUSIONS: Animals with metabolic syndrome had significant autophagy down-regulation in chronically ischemic myocardium. Interestingly, metformin treatment in the context of metabolic syndrome further attenuated the autophagy pathway. These results suggest that metabolic syndrome has a negative effect on autophagy that is not reversed with metformin treatment.
- © 2013 by American Heart Association, Inc.