title: Mitochondrial permeability transition in the diabetic heart: contributions of thiol redox state and mitochondrial calcium to augmented reperfusion injury.
abstract: Mitochondria from diabetic hearts are sensitized to mitochondrial permeability transition pore (PTP) opening, which may be responsible for the increased propensity for cardiac injury in diabetic hearts. The purpose of this study was to determine if redox-dependent PTP opening contributes to augmented injury in diabetic hearts, and if compounds targeted at mitochondrial PTP, ROS, and calcium influx protected diabetic hearts from injury. Hearts from control or streptozotocin-induced diabetic rats were excised for either whole-heart or isolated mitochondria experiments. Myocardial glutathione content was oxidized in diabetic hearts when compared to control, and this translated to increased oxidation of the adenine nucleotide translocase in diabetic hearts. Diabetic mitochondria displayed significantly greater sensitivity to PTP opening than non-diabetic counterparts, which was reversed with the thiol-reducing agent dithiothreitol. The thiol-oxidant diamide increased calcium sensitivity in control, but not diabetic mitochondria. Diabetic animals treated with the mitochondria-targeted ROS suppressing peptide MTP-131 also showed improved resistance to PTP opening. In separate experiments hearts underwent ex vivo ischemia/reperfusion (IR). Diabetic hearts were more susceptible to IR injury, with infarct sizes of 60 ± 4% of the area-at-risk (vs. 46 ± 2% in non-diabetics; P<0.05). Administration of the PTP blocker NIM811 (5 μM), MTP-131 (1 nM) or the mitochondrial calcium uniporter blocker minocycline (1 μM) at the onset of reperfusion reduced infarct sizes in both control and diabetic hearts. These findings suggest that augmented susceptibility to injury in the diabetic heart is mediated by redox-dependent shifts in PTP opening, and that three novel mitochondria-targeted agents administered at reperfusion may be suitable adjuvant reperfusion therapies to attenuate injury in diabetic patients.
authors.affiliation: Department of Kinesiology, Brody School of Medicine, East Carolina University, Greenville NC 27834, USA.
authors.forename: Ruben C
authors.initials: RC
authors.lastname: Sloan
authors.forename: Fatiha
authors.initials: F
authors.lastname: Moukdar
authors.forename: Chad R
authors.initials: CR
authors.lastname: Frasier
authors.forename: Hetal D
authors.initials: HD
authors.lastname: Patel
authors.forename: Phillip A
authors.initials: PA
authors.lastname: Bostian
authors.forename: Robert M
authors.initials: RM
authors.lastname: Lust
authors.forename: David A
authors.initials: DA
authors.lastname: Brown
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism*; D002121:Calcium Channel Blockers / Q000494:pharmacology / Q000627:therapeutic use; D020013:Calcium Signaling; D002316:Cardiotonic Agents / Q000494:pharmacology / Q000627:therapeutic use; D016572:Cyclosporine / Q000494:pharmacology / Q000627:therapeutic use; D003921:Diabetes Mellitus, Experimental / Q000150:complications / Q000378:metabolism*; D005978:Glutathione / Q000378:metabolism; D019803:Glutathione Disulfide / Q000378:metabolism; D006321:Heart / Q000187:drug effects / Q000503:physiopathology; D006439:Hemodynamics; D066298:In Vitro Techniques; D008297:Male; D008911:Minocycline / Q000494:pharmacology / Q000627:therapeutic use; D008929:Mitochondria, Heart / Q000187:drug effects / Q000378:metabolism*; D000226:Mitochondrial ADP, ATP Translocases / Q000378:metabolism; D033681:Mitochondrial Membrane Transport Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D000083162:Mitochondrial Permeability Transition Pore; D015428:Myocardial Reperfusion Injury / Q000209:etiology / Q000378:metabolism* / Q000473:pathology / Q000517:prevention & control; D009842:Oligopeptides / Q000494:pharmacology* / Q000627:therapeutic use; D010084:Oxidation-Reduction; D010539:Permeability; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D002121:Calcium Channel Blockers; D002316:Cardiotonic Agents; D033681:Mitochondrial Membrane Transport Proteins; D000083162:Mitochondrial Permeability Transition Pore; D009842:Oligopeptides; C506540:arginyl-2,'6'-dimethyltyrosyl-lysyl-phenylalaninamide; D016572:Cyclosporine; D000226:Mitochondrial ADP, ATP Translocases; C090438:(melle-4)cyclosporin; D008911:Minocycline; D005978:Glutathione; D002118:Calcium; D019803:Glutathione Disulfide