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Published on: March 9, 2019
Pathophysiological consequences of TAT-HKII peptide administration are independent of impaired vascular function and
Rianne Nederlof1, Chaoqin Xie, Otto Eerbeek
1Department of Anesthesiology, Laboratory of Experimental Intensive Care and Anesthesiology, Academic Medical Center, Amsterdam, The Netherlands.
Insights
High-dose TAT-hexokinase II (HKII) peptide causes heart dysfunction, but not via vasoconstriction. Low-dose TAT-HKII blocks heart protection without causing ischemia, highlighting HKII
Area of Science:
- Cardiovascular Biology
- Mitochondrial Biochemistry
- Ischemia-Reperfusion Injury
Background:
- Hexokinase II (HKII) dissociation from mitochondria affects heart function.
- Low-dose TAT-HKII prevents cardioprotection; high-dose causes dysfunction.
- Previous studies suggested vasoconstriction and ischemia mediate high-dose TAT-HKII effects.
Purpose of the Study:
- To investigate if vascular dysfunction and ischemia cause the negative effects of TAT-HKII on heart function.
- To determine the mechanism behind TAT-HKII's impact on myocardial integrity.
Main Methods:
- Mitochondrial membrane potential (ΔΨm) imaging
- Optical action potential mapping
- Lactate and lactate dehydrogenase analysis
- Nicotinamide adenine dinucleotide epifluorescence
- Electron microscopy
Main Results:
- High-dose TAT-HKII-induced myocardial dysfunction is not due to impaired vascular function or ischemia.
- Low-dose TAT-HKII abrogates ischemic preconditioning's protective effects without causing ischemia.
- Direct evidence refutes the vasoconstriction-ischemia hypothesis for TAT-HKII's deleterious cardiac effects.
Conclusions:
- The effects of TAT-HKII on cardiac function are not mediated by vascular dysfunction or ischemia.
- Mitochondria-bound HKII is a critical regulator of cardiac function.
- HKII plays a key role in ischemia-reperfusion injury and ischemic preconditioning-mediated cardioprotection.
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.
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