Reducing mitochondrial bound hexokinase II mediates transition from non-injurious into injurious ischemia/reperfusion of the intact heart

Ischemia/reperfusion (I/R) of the heart becomes injurious when duration of the ischemic insult exceeds a certain threshold (approximately ≥20 min). Mitochondrial bound hexokinase II (mtHKII) protects against I/R injury, with the amount of mtHKII correlating with injury. Here, we examine whether mtHK...

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Bibliographic Details
Published in:	Journal of physiology and biochemistry Vol. 73; no. 3; pp. 323 - 333
Main Authors:	Nederlof, Rianne, Gürel-Gurevin, Ebru, Eerbeek, Otto, Xie, Chaoqin, Deijs, G. Sjoerd, Konkel, Moritz, Hu, Jun, Weber, Nina C., Schumacher, Cees A., Baartscheer, Antonius, Mik, Egbert G., Hollmann, Markus W., Akar, Fadi G., Zuurbier, Coert J.
Format:	Journal Article
Language:	English
Published:	Dordrecht Springer Netherlands 01-08-2016 Springer Nature B.V
Subjects:	Adenosine Triphosphate - metabolism Animal Physiology Animals Biomedical and Life Sciences Biomedicine Detaching Energy Metabolism Exposure Fluorescence Gangrene Heart Heart diseases Hexokinase Hexokinase - metabolism Human Physiology Injury prevention Ischemia Male Mitochondria Mitochondria, Heart - enzymology Myocardial Reperfusion Injury - enzymology Myocardium - enzymology Necrosis Original Original Article Oxidation-Reduction Oxygen Consumption Oxygen tension Phosphocreatine - metabolism Polymerase chain reaction Protein Binding Protein Transport Protoporphyrin Protoporphyrin IX Rats, Wistar Reactive oxygen species Reactive Oxygen Species - metabolism Recovery Recovery of function Reperfusion Rodents Oxygen consumption Reactive oxygen species Ischemia/reperfusion injury Hexokinase
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Summary:	Ischemia/reperfusion (I/R) of the heart becomes injurious when duration of the ischemic insult exceeds a certain threshold (approximately ≥20 min). Mitochondrial bound hexokinase II (mtHKII) protects against I/R injury, with the amount of mtHKII correlating with injury. Here, we examine whether mtHKII can induce the transition from non-injurious to injurious I/R, by detaching HKII from mitochondria during a non-injurious I/R interval. Additionally, we examine possible underlying mechanisms (increased reactive oxygen species (ROS), increased oxygen consumption (MVO 2 ) and decreased cardiac energetics) associated with this transition. Langendorff perfused rat hearts were treated for 20 min with saline, TAT-only or 200 nM TAT-HKII, a peptide that translocates HKII from mitochondria. Then, hearts were exposed to non-injurious 15-min ischemia, followed by 30-min reperfusion. I/R injury was determined by necrosis (LDH release) and cardiac mechanical recovery. ROS were measured by DHE fluorescence. Changes in cardiac respiratory activity (cardiac MVO 2 and efficiency and mitochondrial oxygen tension (mitoPO 2 ) using protoporphyrin IX) and cardiac energetics (ATP, PCr, ∆G ATP ) were determined following peptide treatment. When exposed to 15-min ischemia, control hearts had no necrosis and 85% recovery of function. Conversely, TAT-HKII treatment resulted in significant LDH release and reduced cardiac recovery (25%), indicating injurious I/R. This was associated with increased ROS during ischemia and reperfusion. TAT-HKII treatment reduced MVO 2 and improved energetics (increased PCr) before ischemia, without affecting MVO 2 /RPP ratio or mitoPO 2 . In conclusion, a reduction in mtHKII turns non-injurious I/R into injurious I/R. Loss of mtHKII was associated with increased ROS during ischemia and reperfusion, but not with increased MVO 2 or decreased cardiac energetics before damage occurs.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	1138-7548 1877-8755
DOI:	10.1007/s13105-017-0555-3