The Cardioprotective Effect of Combined Therapy With α-Lipoic Acid Preconditioning and Ischemic Postconditioning Is Mediated by the Improvement of Autophagy Flux and Mitochondrial Function in Myocardial Reperfusion Injury of Diabetic Rats

Abstract Investigating the interaction of diabetes with ischemic postconditioning (IPostC)-associated cardioprotection in myocardial ischemia/reperfusion (I/R) damage is of great clinical importance. The present work was performed to evaluate the combined effects of α-lipoic acid (LA) and IPostC on autophagy flux and mitochondrial function following myocardial I/R damage in type-II diabetic rats. Diabetes with duration of 12 weeks was induced by high-fat diet/low dose of streptozotocin. LA (500 mg/kg/day) was administered orally in diabetic rats for 5 weeks before I/R. The hearts were removed and mounted on Langendorff apparatus. I/R was induced through the ligation of left anterior descending coronary artery for 35 min and reperfusion for 60 min. IPostC was applied immediately at the onset of the reperfusion. Lastly, myocardial infarct size (IS), autophagy markers at both gene and protein levels, and mitochondrial ROS production and membrane potential were assessed. Combination of LA and IPostC significantly decreased the IS of diabetic hearts (P < 0.05). IPostC alone could not significantly decrease p62 gene and protein expressions, and mitochondrial membrane depolarization in diabetic hearts. However, combination of LA and IPostC more significantly decreased LC3 and p62 gene expressions (P < 0.01), LC3II/LC3I and p62 protein expressions (P < 0.01), and mitochondrial ROS generation and membrane depolarization (P < 0.01) in diabetic hearts. Pretreatment with LA in diabetic rats notably restored cardioprotection by IPostC via modulation of autophagy flux and restoring mitochondrial function. This combined conditioning might be an effective strategy to diminish I/R injury in diabetic hearts.