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Int J Cardiol. 2016 Jan 1;202:13-20. doi: 10.1016/j.ijcard.2015.08.111. Epub 2015 Aug 10.

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

Author information

1
Department of Physiology-HeartOtago, University of Otago, New Zealand.
2
School of Clinical Sciences, Bristol Heart Institute, University of Bristol, Bristol, United Kingdom.
3
Department of Cardiovascular Surgery, University of Otago, New Zealand.
4
Department of Anatomy, University of Otago, New Zealand.
5
Department of Surgery, University of Otago, New Zealand.
6
Department of Physiology-HeartOtago, University of Otago, New Zealand. Electronic address: rajesh.katare@otago.ac.nz.

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.

KEYWORDS:

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

PMID:
26386349
DOI:
10.1016/j.ijcard.2015.08.111
[Indexed for MEDLINE]

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