title: Type-2 diabetes increases autophagy in the human heart through promotion of Beclin-1 mediated pathway.
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.
  
  
  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.
authors.affiliation: Department of Physiology-HeartOtago, University of Otago, New Zealand.
authors.forename: Pujika Emani
authors.initials: PE
authors.lastname: Munasinghe
authors.affiliation: School of Clinical Sciences, Bristol Heart Institute, University of Bristol, Bristol, United Kingdom.
authors.forename: Federica
authors.initials: F
authors.lastname: Riu
authors.affiliation: Department of Physiology-HeartOtago, University of Otago, New Zealand.
authors.forename: Parul
authors.initials: P
authors.lastname: Dixit
authors.affiliation: Department of Physiology-HeartOtago, University of Otago, New Zealand.
authors.forename: Midori
authors.initials: M
authors.lastname: Edamatsu
authors.affiliation: Department of Cardiovascular Surgery, University of Otago, New Zealand.
authors.forename: Pankaj
authors.initials: P
authors.lastname: Saxena
authors.affiliation: Department of Physiology-HeartOtago, University of Otago, New Zealand.
authors.forename: Nathan S J
authors.initials: NS
authors.lastname: Hamer
authors.affiliation: Department of Cardiovascular Surgery, University of Otago, New Zealand.
authors.forename: Ivor F
authors.initials: IF
authors.lastname: Galvin
authors.affiliation: Department of Cardiovascular Surgery, University of Otago, New Zealand.
authors.forename: Richard W
authors.initials: RW
authors.lastname: Bunton
authors.affiliation: Department of Anatomy, University of Otago, New Zealand.
authors.forename: Sharon
authors.initials: S
authors.lastname: Lequeux
authors.affiliation: Department of Surgery, University of Otago, New Zealand.
authors.forename: Greg
authors.initials: G
authors.lastname: Jones
authors.affiliation: Department of Physiology-HeartOtago, University of Otago, New Zealand.
authors.forename: Regis R
authors.initials: RR
authors.lastname: Lamberts
authors.affiliation: School of Clinical Sciences, Bristol Heart Institute, University of Bristol, Bristol, United Kingdom.
authors.forename: Costanza
authors.initials: C
authors.lastname: Emanueli
authors.affiliation: School of Clinical Sciences, Bristol Heart Institute, University of Bristol, Bristol, United Kingdom.
authors.forename: Paolo
authors.initials: P
authors.lastname: Madeddu
authors.affiliation: Department of Physiology-HeartOtago, University of Otago, New Zealand. Electronic address: rajesh.katare@otago.ac.nz.
authors.forename: Rajesh
authors.initials: R
authors.lastname: Katare
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000235:genetics; D051017:Apoptosis Regulatory Proteins / Q000096:biosynthesis / Q000235:genetics*; D001343:Autophagy / Q000235:genetics; D000071186:Beclin-1; D015153:Blotting, Western; D002478:Cells, Cultured; D003921:Diabetes Mellitus, Experimental; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D058065:Diabetic Cardiomyopathies / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D005260:Female; D005786:Gene Expression Regulation; D006801:Humans; D020287:In Situ Nick-End Labeling; D008297:Male; D008565:Membrane Proteins / Q000096:biosynthesis / Q000235:genetics*; D051379:Mice; D008820:Mice, Obese; D008854:Microscopy, Electron; D009206:Myocardium / Q000378:metabolism* / Q000648:ultrastructure; D012313:RNA / Q000235:genetics; D034741:RNA, Small Interfering / Q000235:genetics; D051381:Rats; D011924:Rats, Zucker; D015398:Signal Transduction / Q000235:genetics
chemical_list: D051017:Apoptosis Regulatory Proteins; C491997:BECN1 protein, human; D000071186:Beclin-1; C115010:Becn1 protein, mouse; C512829:Becn1 protein, rat; D008565:Membrane Proteins; D034741:RNA, Small Interfering; D012313:RNA
keywords: Apoptosis; Autophagy; Beclin-1; Diabetes; Heart disease