The role of PTEN in cardioprotection against ischaemia-reperfusion injury.
Doctoral thesis, UCL (University College London).
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.
|Title:||The role of PTEN in cardioprotection against ischaemia-reperfusion injury|
|Open access status:||An open access version is available from UCL Discovery|
|UCL classification:||UCL > School of Life and Medical Sciences > Faculty of Medical Sciences > Medicine (Division of) > Cardiovascular Medicine|
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