P490Diabetes induces maladaptive autophagy in cardiomyocytes and resident cardiac stem cells

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Abstract

Background

Autophagy is essential for the maintenance of cellular homeostasis, but whether autophagy is deregulated becoming a suicidal mechanism during the evolution of diabetic cardiomyopathy remains undetermined.

Objective

To demonstrate the occurrence and mechanisms of maladaptive autophagy in cardiomyocytes (CMs) and resident cardiac stem cells (CSCs) of diabetic hearts. To investigate if Benfotiamine (BFT), a vitamin B1 analogue, showed by us to halt the progression of diabetic cardiomyopathy through the anti-autophagic Akt/Pim-1 signalling pathway, inhibits maladaptive autophagy.

Methods and Results

Diabetes was induced by streptozotocin in CD1 mice. Hearts were harvested 32-weeks later for histology and molecular analyses. In diabetic animals, we found a marked increase in the number of CMs that express the autophagy related protein microtubule-associated protein-1 light chain-II (LC3-II) and are also TUNEL positive (800 ± 40 vs. 24 ± 5 LC3( + )TUNEL( + ) CMs/100,000 CMs in controls, P < 0.001). Sca-1pos CSCs also showed increased LC3-II expression (34 ± 4 vs. 3 ± 0.6 LC3( + )SCa-1( + ) CSCs/100,000 CSCs in controls, P < 0.001). Further analysis of diabetic CSCs revealed a 3-fold increase in reactive oxygen species (ROS) and 6-fold increase in advanced glycation end products (AGE) activity. AGE and ROS are activators of Beclin-1, a key regulator of autophagic cell death. In line, diabetic hearts showed 4.3 ± 0.9 fold increase in beclin-1 expression (P < 0.001 vs. control). Dietary supplementation with BFT, 70mg/kg/day, starting at 5 weeks after diabetes induction, markedly reduced AGE and ROS levels as well as the number of CMs coexpressing autophagy and apoptosis markers (131 ± 16 vs. 800 ± 40 LC3( + )TUNEL( + ) CMs/100,000 CMs in vehicle, P < 0.001). Finally, high glucose (25mM) induced the expression of LC3-II in CD45(-)CD90( + )CD105( + ) CSCs extracted from the atrial appendage of patients undergoing on-pump bypass cardiac surgery and this phenomenon was reverted by BFT (150µM).

Conclusion

These results demonstrate that diabetes induces maladaptive autophagy in cardiomyocytes and CSCs through ROS/AGE mediated activation of beclin-1. Treatments modulating autophagy could be a potential therapeutic approach for alleviation of diabetic cardiomyopathy.

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