title: Cardioprotection during diabetes: the role of mitochondrial DNA.
abstract: BACKGROUND
  Diabetes alters mitochondrial bioenergetics and consequently disrupts cardioprotective signaling. The authors investigated whether mitochondrial DNA (mtDNA) modulates anesthetic preconditioning (APC) and cardiac susceptibility to ischemia-reperfusion injury by using two strains of rats, both sharing nuclear genome of type 2 diabetes mellitus (T2DN) rats and having distinct mitochondrial genomes of Wistar and fawn-hooded hypertensive (FHH) rat strains (T2DN(mtWistar) and T2DN(mtFHH), respectively).
  
  
  METHODS
  Myocardial infarct size was measured in Wistar, T2DN(mtWistar), and T2DN(mtFHH) rats with or without APC (1.4% isoflurane) in the presence or absence of antioxidant N-acetylcysteine. Flavoprotein fluorescence intensity, a marker of mitochondrial redox state, 5-(and-6)-chloromethyl-2',7'-dichlorofluorescein fluorescence intensity, a marker of reactive oxygen species generation, and mitochondrial permeability transition pore opening were assessed in isolated rat ventricular cardiomyocytes with or without isoflurane (0.5 mmol/l).
  
  
  RESULTS
  Myocardial infarct size was decreased by APC in Wistar and T2DN(mtWistar) rats (to 42 ± 6%, n = 8; and 44 ± 7%, n = 8; of risk area, respectively) compared with their respective controls (60 ± 3%, n = 6; and 59 ± 9%, n = 7), but not in T2DN(mtFHH) rats (60 ± 2%, n = 8). N-acetylcysteine applied during isoflurane treatment restored APC in T2DN(mtFHH) (39 ± 6%, n = 7; and 38 ± 5%, n = 7; 150 and 75 mg/kg N-acetylcysteine, respectively), but abolished protection in control rats (54 ± 8%, n = 6). Similar to the data on infarct size, APC delayed mitochondrial permeability transition pore opening in T2DN(mtWistar) but not in T2DN(mtFHH) cardiomyocytes. Isoflurane increased flavoprotein and 5-(and-6)-chloromethyl-2',7'-dichlorofluorescein fluorescence intensity in all rat strains, with the greatest effect in T2DN(mtFHH) cardiomyocytes.
  
  
  CONCLUSIONS
  Differences in the mitochondrial genome modulate isoflurane-induced generation of reactive oxygen species which translates into differential susceptibility to APC and ischemia-reperfusion injury in diabetic rats.
authors.affiliation: From the Department of Anesthesiology (M.M., I.B., M.B., Z.J.B., F.S., D.C.W., and J.R.K.), Department of Pharmacology and Toxicology (M.B., D.C.W., and J.R.K.), and Department of Physiology (Z.J.B.), Medical College of Wisconsin, Milwaukee, Wisconsin; and The Human and Molecular Genetics Center, Medical College of Wisconsin, Milwaukee, Wisconsin (J.L.).
authors.forename: Maria
authors.initials: M
authors.lastname: Muravyeva
authors.forename: Ines
authors.initials: I
authors.lastname: Baotic
authors.forename: Martin
authors.initials: M
authors.lastname: Bienengraeber
authors.forename: Jozef
authors.initials: J
authors.lastname: Lazar
authors.forename: Zeljko J
authors.initials: ZJ
authors.lastname: Bosnjak
authors.forename: Filip
authors.initials: F
authors.lastname: Sedlic
authors.forename: David C
authors.initials: DC
authors.lastname: Warltier
authors.forename: Judy R
authors.initials: JR
authors.lastname: Kersten
mesh_terms: D000111:Acetylcysteine / Q000378:metabolism / Q000494:pharmacology; D018685:Anesthetics, Inhalation / Q000378:metabolism / Q000494:pharmacology; D000818:Animals; D004272:DNA, Mitochondrial / Q000378:metabolism*; D003924:Diabetes Mellitus, Type 2 / Q000150:complications* / Q000378:metabolism / Q000503:physiopathology; D004195:Disease Models, Animal; D016166:Free Radical Scavengers / Q000378:metabolism / Q000494:pharmacology; D019157:Ischemic Preconditioning, Myocardial / Q000379:methods*; D007530:Isoflurane / Q000378:metabolism / Q000494:pharmacology; D008297:Male; D008929:Mitochondria, Heart / Q000378:metabolism*; D009203:Myocardial Infarction / Q000150:complications* / Q000378:metabolism / Q000503:physiopathology; D015428:Myocardial Reperfusion Injury / Q000378:metabolism / Q000517:prevention & control*; D009206:Myocardium / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D017382:Reactive Oxygen Species / Q000378:metabolism
chemical_list: D018685:Anesthetics, Inhalation; D004272:DNA, Mitochondrial; D016166:Free Radical Scavengers; D017382:Reactive Oxygen Species; D007530:Isoflurane; D000111:Acetylcysteine