Activation of the PI3K/AKT pathway protects the heart from ischaemia-reperfusion injury.
Phosphatase and Tensin Homolog deleted on Chromosome10 (PTEN) is a negative regulator
of this pathway. The hypothesis on which this thesis was based stated that inhibition of PTEN
would confer protection against ischaemia-reperfusion injury. PTEN was reduced using: 1) a
PTEN inhibitor, bpV(HOpic), 2) a mouse model of PTEN haploinsufficiency and 3) PTEN
siRNA. The effects of PTEN reduction on ischaemia-reperfusion injury were investigated by
using: 1) an isolated perfused heart model of ischaemia-reperfusion injury, 2) an isolated
cardiomyocyte model of ROS induced mitochondria damage and 3) a cellular model of
hypoxia-reoxygenation injury. No protection against ischaemia-reperfusion was observed in
isolated perfused myocardium from C57BL/J6 mice, which were perfused with bpV(HOpic), or
from PTEN+/-mice. Likewise, no protection against ROS induced mitochondrial damage was
observed in isolated cardiomyocytes from the PTEN+/- mice. In these models an increase in
AKT activity was recorded, however, this was not sufficient to confer cardioprotection.
Similarly, H9c2 rat myoblast cells, silenced for PTEN expression using siRNA, were not
protected against hypoxia-reoxygenation injury. Nevertheless, in isolated C57BL/J6 hearts
perfused with bpV(HOpic) and in myocardium from PTEN+/- mice, when the PI3K/AKT
pathway was stimulated by the cardioprotective intervention of ischaemic preconditioning a
reduced threshold for protection was achieved. To conclude, the level of PTEN inhibition
achieved in this study was not sufficient to bestow protection against simulated ischaemiareperfusion
injury. However, it appears that reductions in PTEN can increase the sensitivity
towards cardioprotection
