Advanced glycation end-products impair Na+/K+-ATPase activity in diabetic cardiomyopathy: Role of the adenosine monophosphate-activated protein kinase/sirtuin 1 pathway

1. Decreased Na+/K+-ATPase activity, and both sirtuin 1 (SIRT1) and adenosine monophosphate-activated protein kinase (AMPK) have been reported to be involved in the development of diabetic cardiomyopathy (DCM). 2. The present study aimed to investigate the advanced glycation end-products (AGE) that impair Na+/K+-ATPase stability by regulating the AMPK/SIRT1 pathway during progression of DCM. 3. To study type 1 diabetic mellitus (T1DM), a disease model in rats was established by a single intraperitoneal injection of streptozotocin (STZ; 65 mg/kg), and neonatal rat cardiomyocytes were also cultured. Heart function was detected by Doppler, and SIRT1 and AMPK protein expression were detected by immunohistochemistry and western blotting. Na+/K+-ATPase activity was also monitored. 4. Using in vivo rat models of DCM, we showed that Na+/K+-ATPase activity decreased when both AMPK and SIRT1 expression were downregulated. In vitro, AGE impaired Na+/K+-ATPase activity and decreased the AMPK and SIRT1 expression. 5. Sirtuin 1 overexpression increased Na+/K+-ATPase activity. 5-aminoimidazole-4-carboxamide-3-ribonucleoside (AICAR) upregulated SIRT1 expression and increased Na+/K+-ATPase activity, which could be partially abolished by splitomicin. 6. Our results suggest that the dysfunction of DCM is related to AGE-induced Na+/K+-ATPase activity impairment through a mechanism involving the AMPK/SIRT1 pathway.