title: Loss of Intralipid®- but not sevoflurane-mediated cardioprotection in early type-2 diabetic hearts of fructose-fed rats: importance of ROS signaling.
abstract: BACKGROUND
  Insulin resistance and early type-2 diabetes are highly prevalent. However, it is unknown whether Intralipid® and sevoflurane protect the early diabetic heart against ischemia-reperfusion injury.
  
  
  METHODS
  Early type-2 diabetic hearts from Sprague-Dawley rats fed for 6 weeks with fructose were exposed to 15 min of ischemia and 30 min of reperfusion. Intralipid® (1%) was administered at the onset of reperfusion. Peri-ischemic sevoflurane (2 vol.-%) served as alternative protection strategy. Recovery of left ventricular function was recorded and the activation of Akt and ERK 1/2 was monitored. Mitochondrial function was assessed by high-resolution respirometry and mitochondrial ROS production was measured by Amplex Red and aconitase activity assays. Acylcarnitine tissue content was measured and concentration-response curves of complex IV inhibition by palmitoylcarnitine were obtained.
  
  
  RESULTS
  Intralipid® did not exert protection in early diabetic hearts, while sevoflurane improved functional recovery. Sevoflurane protection was abolished by concomitant administration of the ROS scavenger N-2-mercaptopropionyl glycine. Sevoflurane, but not Intralipid® produced protective ROS during reperfusion, which activated Akt. Intralipid® failed to inhibit respiratory complex IV, while sevoflurane inhibited complex I. Early diabetic hearts exhibited reduced carnitine-palmitoyl-transferase-1 activity, but palmitoylcarnitine could not rescue protection and enhance postischemic functional recovery. Cardiac mitochondria from early diabetic rats exhibited an increased content of subunit IV-2 of respiratory complex IV and of uncoupling protein-3.
  
  
  CONCLUSIONS
  Early type-2 diabetic hearts lose complex IV-mediated protection by Intralipid® potentially due to a switch in complex IV subunit expression and increased mitochondrial uncoupling, but are amenable to complex I-mediated sevoflurane protection.
authors.affiliation: Cardiovascular Research Centre, University of Alberta, Edmonton, Alberta, Canada.
authors.forename: Phing-How
authors.initials: PH
authors.lastname: Lou
authors.affiliation: Department of Anesthesiology & Pain Medicine, University of Alberta, Edmonton, Alberta, Canada.
authors.forename: Eliana
authors.initials: E
authors.lastname: Lucchinetti
authors.affiliation: Department of Anesthesiology & Pain Medicine, University of Alberta, Edmonton, Alberta, Canada.
authors.forename: Liyan
authors.initials: L
authors.lastname: Zhang
authors.affiliation: Department of Clinical Chemistry, University Children's Hospital Zurich, Zurich, Switzerland.
authors.forename: Andreas
authors.initials: A
authors.lastname: Affolter
authors.affiliation: Department of Pharmacology, University of Alberta, Edmonton, Alberta, Canada.
authors.forename: Manoj
authors.initials: M
authors.lastname: Gandhi
authors.affiliation: Department of Clinical Chemistry, University Children's Hospital Zurich, Zurich, Switzerland.
authors.forename: Martin
authors.initials: M
authors.lastname: Hersberger
authors.affiliation: Campus Saint-Jean, University of Alberta, Edmonton, Alberta, Canada.
authors.forename: Blair E
authors.initials: BE
authors.lastname: Warren
authors.affiliation: Campus Saint-Jean, University of Alberta, Edmonton, Alberta, Canada.
authors.forename: Hélène
authors.initials: H
authors.lastname: Lemieux
authors.affiliation: Coppin Center for Organic Synthesis, Coppin State University, Baltimore, Maryland, United States of America.
authors.forename: Hany F
authors.initials: HF
authors.lastname: Sobhi
authors.affiliation: Department of Pharmacology, University of Alberta, Edmonton, Alberta, Canada.
authors.forename: Alexander S
authors.initials: AS
authors.lastname: Clanachan
authors.affiliation: Department of Anesthesiology & Pain Medicine, University of Alberta, Edmonton, Alberta, Canada.
authors.forename: Michael
authors.initials: M
authors.lastname: Zaugg
mesh_terms: D000818:Animals; D002316:Cardiotonic Agents / Q000627:therapeutic use*; D003924:Diabetes Mellitus, Type 2 / Q000150:complications* / Q000378:metabolism; D003576:Electron Transport Complex IV / Q000378:metabolism; D004655:Emulsions / Q000627:therapeutic use; D005217:Fat Emulsions, Intravenous / Q000627:therapeutic use*; D005632:Fructose / Q000378:metabolism; D006321:Heart / Q000187:drug effects*; D007473:Ion Channels / Q000378:metabolism; D008297:Male; D008738:Methyl Ethers / Q000627:therapeutic use*; D024101:Mitochondrial Proteins / Q000378:metabolism; D015428:Myocardial Reperfusion Injury / Q000188:drug therapy* / Q000378:metabolism; D010743:Phospholipids / Q000627:therapeutic use*; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000378:metabolism; D000077149:Sevoflurane; D015398:Signal Transduction / Q000187:drug effects; D013024:Soybean Oil / Q000627:therapeutic use*; D000071247:Uncoupling Protein 3
chemical_list: D002316:Cardiotonic Agents; D004655:Emulsions; D005217:Fat Emulsions, Intravenous; D007473:Ion Channels; D008738:Methyl Ethers; D024101:Mitochondrial Proteins; D010743:Phospholipids; D017382:Reactive Oxygen Species; C000604394:Ucp3 protein, rat; D000071247:Uncoupling Protein 3; C545823:soybean oil, phospholipid emulsion; D005632:Fructose; D000077149:Sevoflurane; D013024:Soybean Oil; D003576:Electron Transport Complex IV