title: Hexokinase II and reperfusion injury: TAT-HK2 peptide impairs vascular function in Langendorff-perfused rat hearts.
abstract: BACKGROUND
  Mitochondrial-bound hexokinase II (HK2) was recently proposed to play a crucial role in the normal functioning of the beating heart and to be necessary to maintain mitochondrial membrane potential. However, our own studies confirmed that mitochondria from ischemic rat hearts were HK2-depleted, yet showed no indication of depolarization and responded normally to ADP.
  
  
  OBJECTIVE
  To establish whether the human TAT-HK2 peptide used to dissociate mitochondrial-bound HKII in the Langendorff-perfused heart may exert its effects indirectly by impairing coronary function.
  
  
  RESULTS
  Ischemic preconditioning was blocked in rat hearts perfused with 2.5 µmol/L TAT-HK2 before ischemia or at the onset of reperfusion. However, TAT-HK2 also decreased the phosphocreatine:ATP ratio that correlated with reduced rate pressure product and increased diastolic pressure. These effects were preceded by increased aortic pressure (Langendorff constant flow) or decreased coronary flow (Langendorff constant pressure), which was also observed, albeit less pronounced, at 200 nmol/L TAT-HK2 and was prevented by coperfusion with the NO-donor diethylamine NONOate. Mitochondria from TAT-HK2-perfused hearts showed no loss of bound HK2, unlike mitochondria from ischemic hearts where the expected loss was prevented by ischemic preconditioning.
  
  
  CONCLUSIONS
  In the perfused rat heart, TAT-HK2 should be used with caution and careful attention to dosage because some of its effects may be mediated by vasoconstriction of the coronary vasculature rather than dissociation of HK2 from myocyte mitochondria.
authors: School of Biochemistry and the Bristol Heart Institute, University of Bristol, Bristol, UK.
authors: Philippe
authors: P
authors: Pasdois
authors: Joanne E
authors: JE
authors: Parker
authors: Elinor J
authors: EJ
authors: Griffiths
authors: Andrew P
authors: AP
authors: Halestrap
mesh_terms: D000818:Animals; D003326:Coronary Circulation / Q000187:drug effects / Q000502:physiology*; D015696:Gene Products, tat / Q000008:administration & dosage* / Q000633:toxicity; D006439:Hemodynamics / Q000187:drug effects / Q000502:physiology; D006593:Hexokinase / Q000008:administration & dosage*; D008297:Male; D015428:Myocardial Reperfusion Injury / Q000139:chemically induced* / Q000503:physiopathology; D010477:Perfusion / Q000379:methods*; D051381:Rats; D017208:Rats, Wistar; D014661:Vasoconstriction / Q000187:drug effects / Q000502:physiology*
chemical_list: D015696:Gene Products, tat; D006593:Hexokinase