Lou 2014b PLoS One
|Lou PH, Lucchinetti E, Zhang L, Affolter A, Gandhi M, Hersberger M, Warren BE, Lemieux H, Sobhi HF, Clanachan AS, Zaugg M (2014) Loss of Intralipid®- but not sevoflurane-mediated cardioprotection in early type-2 diabetic hearts of fructose-fed rats: importance of ROS signaling. PLoS One 9:e104971.|
Abstract: 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.
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.
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.
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.
• Keywords: Amplex Red
Labels: MiParea: Respiration, Pharmacology;toxicology Pathology: Diabetes Stress:Ischemia-reperfusion Organism: Rat Tissue;cell: Heart Preparation: Permeabilized tissue
Coupling state: LEAK Pathway: F, N, S, CIV HRR: Oxygraph-2k