Type-2 diabetes increases autophagy in the human heart through promotion of Beclin-1 mediated pathway

Pujika Emani Munasinghe, Federica Riu, Parul Dixit, Midori Edamatsu, Pankaj Saxena, Nathan S.J. Hamer, Ivor F. Galvin, Richard W. Bunton, Sharon Lequeux, Greg Jones, Regis R. Lamberts, Costanza Emanueli, Paolo Madeddu, Rajesh Katare

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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.

Original languageEnglish
Pages (from-to)13-20
Number of pages8
JournalInternational Journal of Cardiology
Volume202
DOIs
Publication statusPublished - Jan 1 2016

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Keywords

  • Apoptosis
  • Autophagy
  • Beclin-1
  • Diabetes
  • Heart disease

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine

Cite this

Munasinghe, P. E., Riu, F., Dixit, P., Edamatsu, M., Saxena, P., Hamer, N. S. J., Galvin, I. F., Bunton, R. W., Lequeux, S., Jones, G., Lamberts, R. R., Emanueli, C., Madeddu, P., & Katare, R. (2016). Type-2 diabetes increases autophagy in the human heart through promotion of Beclin-1 mediated pathway. International Journal of Cardiology, 202, 13-20. https://doi.org/10.1016/j.ijcard.2015.08.111