Abstract 18760: Homeostatic Intracellular Repair Response (HIR2) is Affected by Glycemic Control in Diabetics Undergoing Cardiac Surgery
Background: We previously reported that HIR2 is activated in the human heart during cardiac surgery. The mechanism underlying HIR2 is adaptive autophagy, a beneficial stress response to ischemia, hypoxia, and nutritional depletion. It is a process that eliminates damaged mitochondria and protein aggregates. Preclinical studies in animal models have shown that HIR2 is impaired in the setting metabolic syndrome. To confirm our previous clinical findings and test the hypothesis that HIR2 is altered in patients with Type II diabetes (T2DM), autophagy was examined in heart tissue obtained from a cohort of patients with and without the disease.
Methods: Biopsies of the right atrium were obtained before initiation and after weaning from cardiopulmonary bypass in 19 patients undergoing conventional cardiac surgery. The Society of Thoracic Surgeons’ database was used to identify individuals with T2DM (n=8). HbA1c was used as a measure of diabetic control. Autophagy was measured by immunoblotting for Beclin-1, LC3, Atg5-12, and p62, and normalized to actin levels. The pre-post difference in p62 (Δp62) was used to assess autophagic flux.
Results: Consistent with previously observed, heart surgery was associated with a significant reduction (all p < 0.01) in Beclin-1 (1.18 ± 0.18 vs. 1.73 ± 0.24), Atg5-12 (0.74 ± 0.10 ± vs.1.11 ± 0.14), and p62 (0.89 ± 0.11 vs. 1.51 ± 0.20), but not LC3. As shown below, depletion of p62 during surgery significantly correlated with Atg5-12 and Beclin-1 across all patients. Notably, in diabetics there was a decrease in the magnitude of the cardiac HIR2 response (Δp62) as a function of glycemic control (HbA1c).
Conclusion: These results confirm our previous findings indicating a robust activation of HIR2 in patients undergoing cardiac surgery. Importantly, in patients with T2DM this adaptive response appears to be substantially blunted, and may explain, in part, the increased morbidity and mortality associated with this at-risk patient population.
- © 2013 by American Heart Association, Inc.