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

• Rianne Nederlof ^[1] ; Ebru Gürel-Gurevin ^[1] ; Otto Eerbeek ^[1] ; Chaoqin Xie ^[3] ; G. Sjoerd Deijs ^[1] ; Moritz Konkel ^[1] ; Jun Hu ^[3] ; Nina C. Weber ^[1] ; Cees A. Schumacher ^[1] ; Antonius Baartscheer ^[1] ; Egbert G. Mik ^[2] ; Markus W. Hollmann ^[1] ; Fadi G. Akar ^[3] ; Coert J. Zuurbier ^[1]
  1. [1] Academic Medical Center

     Academic Medical Center

     Países Bajos

     
  2. [2] Erasmus University Medical Center

     Erasmus University Medical Center

     Países Bajos

     
  3. [3] Mt. Sinai School of Medicine, Estados Unidos

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• Localización: Journal of physiology and biochemistry, ISSN-e 1877-8755, ISSN 1138-7548, Vol. 73, Nº. 3 (August 2017), 2017 (Ejemplar dedicado a: CTPIOD meeting (Contribution To Progress in Obesity and Diabetes Research) 2016), págs. 323-333
• Idioma: inglés
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  • 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 (MVO2) 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 MVO2 and efficiency and mitochondrial oxygen tension (mitoPO2) using protoporphyrin IX) and cardiac energetics (ATP, PCr, ∆GATP) 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 MVO2 and improved energetics (increased PCr) before ischemia, without affecting MVO2/RPP ratio or mitoPO2. 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 MVO2 or decreased cardiac energetics before damage occurs.