ABSTRACT
BACKGROUND: Diabetes promotes progressive loss of cardiac cells, which are replaced by a fibrotic matrix, resulting in the loss of cardiac function. In the current study we sought to identify if excessive autophagy plays a major role in inducing this progressive loss. METHODS AND RESULTS: Immunofluorescence and western blotting analysis of the right atrial appendages collected from diabetic and non-diabetic patients undergoing coronary artery bypass graft surgery showed a marked increase in the level of autophagy in the diabetic heart, as evidenced by increased expression of autophagy marker LC3B-II and its mediator Beclin-1 and decreased expression of p62, which incorporates into autophagosomes to be efficiently degraded. Moreover, a marked activation of pro-apoptotic caspase-3 was observed. Electron microscopy showed increased autophagosomes in the diabetic heart. In vivo measurement of autophagic flux by choloroquine injection resulted in further enhancement of LC3B-II in the diabetic myocardium, confirming increased autophagic activity in the type-2 diabetic heart. Importantly, in-vitro genetic depletion of beclin-1 in high glucose treated adult rat cardiomyocytes markedly inhibited the level of autophagy and subsequent apoptotic cell death. CONCLUSIONS: These findings demonstrate the pathological role of autophagy in the type-2 diabetic heart, opening up a potentially novel therapeutic avenue for the treatment of diabetic heart disease.
Subject(s)
Apoptosis Regulatory Proteins/genetics , Diabetes Mellitus, Type 2/genetics , Diabetic Cardiomyopathies/genetics , Gene Expression Regulation , Membrane Proteins/genetics , Myocardium/metabolism , Animals , Apoptosis/genetics , Apoptosis Regulatory Proteins/biosynthesis , Autophagy/genetics , Beclin-1 , Blotting, Western , Cells, Cultured , Diabetes Mellitus, Experimental , Diabetes Mellitus, Type 2/metabolism , Diabetes Mellitus, Type 2/pathology , Diabetic Cardiomyopathies/metabolism , Diabetic Cardiomyopathies/pathology , Female , Humans , In Situ Nick-End Labeling , Male , Membrane Proteins/biosynthesis , Mice , Mice, Obese , Microscopy, Electron , Myocardium/ultrastructure , RNA/genetics , RNA, Small Interfering/genetics , Rats , Rats, Zucker , Signal Transduction/geneticsABSTRACT
This data article contains full list of autophagy related genes that are altered in diabetic heart. This article also shows data from in vitro cultured cardiomyocytes that are exposed the high glucose treatment to simulate hyperglycemic state in vitro. The interpretation of these data and further extensive insights into the regulation of SG biogenesis by AMPK can be found in "Type-2 diabetes increases autophagy in the human heart through promotion of Beclin-1 mediated pathway" (Munasinghe et al., in press) [1].
