Document Detail


Pathophysiological consequences of TAT-HKII peptide administration are independent of impaired vascular function and ensuing ischemia.
MedLine Citation:
PMID:  23329797     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
RATIONALE: 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.
METHODS AND 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:
Rianne Nederlof; Chaoqin Xie; Otto Eerbeek; Anneke Koeman; Dan M J Milstein; Markus W Hollmann; Egbert G Mik; Alice Warley; Richard Southworth; Fadi G Akar; Coert J Zuurbier
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Publication Detail:
Type:  Comment; Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  Circulation research     Volume:  112     ISSN:  1524-4571     ISO Abbreviation:  Circ. Res.     Publication Date:  2013 Jan 
Date Detail:
Created Date:  2013-01-18     Completed Date:  2013-03-08     Revised Date:  2014-01-24    
Medline Journal Info:
Nlm Unique ID:  0047103     Medline TA:  Circ Res     Country:  United States    
Other Details:
Languages:  eng     Pagination:  e8-13     Citation Subset:  IM    
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MeSH Terms
Descriptor/Qualifier:
Animals
Coronary Circulation / physiology*
Gene Products, tat / administration & dosage*
Hexokinase / administration & dosage*
Male
Myocardial Reperfusion Injury / chemically induced*
Perfusion / methods*
Vasoconstriction / physiology*
Grant Support
ID/Acronym/Agency:
HL097108/HL/NHLBI NIH HHS; R21 HL097108/HL/NHLBI NIH HHS
Chemical
Reg. No./Substance:
0/Gene Products, tat; EC 2.7.1.1/Hexokinase
Comments/Corrections
Comment On:
Circ Res. 2013 Jan 18;112(2):e3-7   [PMID:  23329796 ]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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