title: Pathophysiological consequences of TAT-HKII peptide administration are independent of impaired vascular function and ensuing ischemia.
abstract: BACKGROUND
  We have shown that partial dissociation of hexokinase II (HKII) from mitochondria in the intact heart using low-dose transactivating transcriptional factor (TAT)-HKII (200 nmol/L) prevents the cardioprotective effects of ischemic preconditioning, whereas high-dose TAT-HKII (10 μmol/L) administration results in rapid myocardial dysfunction, mitochondrial depolarization, and disintegration. In this issue of Circulation Research, Pasdois et al argue that the deleterious effects of TAT-HKII administration on cardiac function are likely because of vasoconstriction and ensuing ischemia.
  
  
  OBJECTIVE
  To investigate whether altered vascular function and ensuing ischemia recapitulate the deleterious effects of TAT-HKII in intact myocardium.
  
  
  RESULTS
  Using a variety of complementary techniques, including mitochondrial membrane potential (ΔΨm) imaging, high-resolution optical action potential mapping, analysis of lactate production, nicotinamide adenine dinucleotide epifluorescence, lactate dehydrogenase release, and electron microscopy, we provide direct evidence that refutes the notion that acute myocardial dysfunction by high-dose TAT-HKII peptide administration is a consequence of impaired vascular function. Moreover, we demonstrate that low-dose TAT-HKII treatment, which abrogates the protective effects of ischemic preconditioning, is not associated with ischemia or ischemic injury.
  
  
  CONCLUSIONS
  Our findings challenge the notion that the effects of TAT-HKII are attributable to impaired vascular function and ensuing ischemia, thereby lending further credence to the role of mitochondria-bound HKII as a critical regulator of cardiac function, ischemia-reperfusion injury, and cardioprotection by ischemic preconditioning.
authors: Department of Anesthesiology, Laboratory of Experimental Intensive Care and Anesthesiology, Academic Medical Center, Amsterdam, The Netherlands.
authors: Rianne
authors: R
authors: Nederlof
authors: Chaoqin
authors: C
authors: Xie
authors: Otto
authors: O
authors: Eerbeek
authors: Anneke
authors: A
authors: Koeman
authors: Dan M J
authors: DM
authors: Milstein
authors: Markus W
authors: MW
authors: Hollmann
authors: Egbert G
authors: EG
authors: Mik
authors: Alice
authors: A
authors: Warley
authors: Richard
authors: R
authors: Southworth
authors: Fadi G
authors: FG
authors: Akar
authors: Coert J
authors: CJ
authors: Zuurbier
mesh_terms: D000818:Animals; D003326:Coronary Circulation / Q000502:physiology*; D015696:Gene Products, tat / Q000008:administration & dosage*; D006593:Hexokinase / Q000008:administration & dosage*; D008297:Male; D015428:Myocardial Reperfusion Injury / Q000139:chemically induced*; D010477:Perfusion / Q000379:methods*; D014661:Vasoconstriction / Q000502:physiology*
chemical_list: D015696:Gene Products, tat; D006593:Hexokinase