title: Cardioprotection in the aging, diabetic heart: the loss of protective Akt signalling.
abstract: OBJECTIVE
  Old age and diabetes are risk factors that often coexist increasing the vulnerability of the heart to the lethal effects of ischaemia-reperfusion injury (IRI). However, to our knowledge, no investigations have examined IRI and cardioprotective signalling in animal models bearing these co-morbidities concomitantly. The ability of the heart to recover following IRI is greatly dependent on its innate cardioprotective potential, in which a central role is played by Akt. We aimed to investigate in an aging diabetic rat model, the susceptibility of the heart to IRI, the achievability of ischaemic preconditioning (IPC) against this lethal event, and the changes in Akt signalling, as the main prosurvival intracellular pathway.
  
  
  RESULTS
  Our data showed that the isolated hearts of aged, diabetic Goto-Kakizaki rats were more susceptible to sub-lethal injury and not amenable to cardioprotection via IPC, compared with younger diabetic rat hearts. Western blot analysis of the heart tissue suggested a chronic up-regulation of Akt phosphorylation, and reduced expression of the mitochondrial regulator PGC-1α and of the anti-oxidant enzyme catalase, potentially due to the Akt up-regulation. Moreover, no further activation of Akt could be achieved following IPC.
  
  
  CONCLUSIONS
  An increased susceptibility to IRI in the aged, diabetic heart could be a consequence of impaired Akt signalling due to chronic Akt phosphorylation. Additional Akt phosphorylation required for IPC protection may therefore not be possible in the aged, diabetic rat heart and may explain why this cardioprotective manoeuvre cannot be achieved in these hearts.
authors.affiliation: The Hatter Cardiovascular Institute, University College London, UK.
authors.forename: Hannah J
authors.initials: HJ
authors.lastname: Whittington
authors.forename: Idris
authors.initials: I
authors.lastname: Harding
authors.forename: Clemency I M
authors.initials: CI
authors.lastname: Stephenson
authors.forename: Robert
authors.initials: R
authors.lastname: Bell
authors.forename: Derek J
authors.initials: DJ
authors.lastname: Hausenloy
authors.forename: Mihaela M
authors.initials: MM
authors.lastname: Mocanu
authors.forename: Derek M
authors.initials: DM
authors.lastname: Yellon
mesh_terms: D000375:Aging / Q000502:physiology*; D000818:Animals; D001786:Blood Glucose / Q000032:analysis; D003920:Diabetes Mellitus / Q000503:physiopathology*; D006442:Glycated Hemoglobin / Q000032:analysis; D006801:Humans; D019157:Ischemic Preconditioning, Myocardial; D008297:Male; D009203:Myocardial Infarction / Q000209:etiology; D015428:Myocardial Reperfusion Injury / Q000209:etiology*; D018384:Oxidative Stress; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D010641:Phenotype; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000502:physiology*; D051381:Rats; D017208:Rats, Wistar; D015398:Signal Transduction / Q000502:physiology*; D014157:Transcription Factors / Q000502:physiology
chemical_list: D001786:Blood Glucose; D006442:Glycated Hemoglobin; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D051057:Proto-Oncogene Proteins c-akt; D014157:Transcription Factors; C501429:Ppargc1a protein, rat; C517652:hemoglobin A1c protein, human
keywords: Age; Akt; Diabetes; Ischaemic preconditioning; Myocardial infarct