Mitochondrial hexokinase and ischemic sensitivity and metabolism of the heart

The general aim of this thesis was to study the effects of hexokinase II (HKII) on cardiac ischemia/reperfusion (I/R) injury and metabolism. In cancer cells, increased binding of both HKI and HKII have been associated with the increased survival rate of these cells. In previous studies it has been observed that binding of HKII to the mitochondria (mtHKII) protects the heart and skeletal muscle against I/R injury. This thesis focused on elucidating the cellular mechanisms by which mtHKII protects the heart against I/R injury. We focused on the effect of a reduction in mtHKII on cardiac metabolism, oxygen consumption, reactive oxygen species and the correlation between HKII and cyclophilin D (CypD). In addition, this thesis studied whether cardioprotection by remote ischemic preconditioning (RIPC) and metformin treatment in cardiac surgical patients is associated with increased amounts of mtHKII.
Taken together, this thesis shows that 1) low doses (200 nM) of the special peptide TAT-HKII can be used to study effects of mtHKII reduction in the heart, 2) a reduction in mtHKII turns non-injurious I/R into injurious I/R and is accompanied by increased reactive oxygen species (ROS) production at reperfusion, and increased energetics at baseline, 3) the cardioprotective effect of CypD deletion might, at least partly, be caused by increased mtHK activity, 4) an acute, but not chronic, decrease in mtHKII affects cardiac metabolism 5) glucose-only is insufficient substrate for the Langendorff perfused mouse heart, and 6) metformin treatment and RIPC in the absence of propofol are not cardioprotective in coronary artery bypass graft (CABG) surgery under the conditions used in this thesis.