Advanced glycation endproducts (AGEs) are a group of heterogeneous compounds accumulated in diabetes due to factors including increased reactive carbohydrate substrate availability, oxidative condition favoring glycation and impaired detoxification . AGEs form and accumulate in aging, renal failure, inflammation and especially diabetes mellitus (DM) . Different cell membrane proteins have been shown to bind AGE and the best characterized receptor for AGE has been named receptors for advanced glycation end products (RAGE) . The interaction between AGEs and RAGE participates in a variety of physiopathological process, including inflammation, carcinogenesis, atherosclerosis, nephropathy and neurodegeneration.
In diabetes mellitus, AGE/RAGE interaction contributes to the development of diabetic complications, including diabetic cardiomyopathy . As one of the major complications of DM, diabetic cardiomyopathy is manifested by progressive heart failure and a poor prognosis in DM patients [5, 6]. Previous studies had documented that the AGEs accumulation induces cardiomocyte apoptosis, leading to caricardiomocyte loss, is one of major mechanism leading to the development of heart dysfunction in diabetic cardiomyopathy .
Apoptosis is the type I programmed cell death pathway. Besides apoptosis, it also exists another type II pathway in mammal cells, namely, autophagy . As a regulator of programmed cell death in mammals, autophagy is triggered by a variety of physiopathological stimuli, e.g. starvation, hypoxia, intracellular stress, hormones, ischemia and metabolism disorders . Autophagy plays an essential role for mammal cell growth, survival, differentiation and development . However, excessive autophagy becomes detrimental to cell fate, causing massive cell death and eventually leading to the function impairment in vivo[11–13].
Accumulating evidence indicate that autophagy is involved in the development of cardiovascular diseases. Autophagy is upregulated in almost all cardiac pathological states, exerting both protective and detrimental functions dependant on the extent of autogphagy . Recent studies revealed massive presence of autophagic death in dead and dying cardiomyocytes in the failing hearts, including dilated cardiomyopathy, valvular heart diasese, hypertensive heart disease and chronic ischemia [15–18]. Notably, the presence of autophagic cardiomyocyte death in failing heart was more prevalent than that of apoptotic cells, suggesting an important role of autophagy in the cardiomocyte loss and heart function deterioration . Excessive cardiac autophagy has been proposed as a maladaptive response that contributes to heart failure progression . Autophagy may transform compensatory cardiac hypertrophy to pump failure. Diminished autophagy is reported to limits cardiac dysfunction in type 1 diabetes .
The phosphatidylinositol 3-phosphate kinase (PI3K) /Akt/mTOR signaling pathway is a well-known pathway involved in the regulation of autophagy in mammal cells . A recent study showed that AGEs can inactivate Akt in rat vascular smooth muscle cells . However, the effect of AGEs on cardiomocyte autophagy remains unknown. In this study, we sought to explore: 1. the role of AGEs in inducing cardiomocyte autophagy; 2. the possible signal pathway involved in the effect of AGEs on cardiomyocyte autophagy.