Tsang, A;
(2006)
Ischaemic postconditioning in normal and type 2 diabetic rat hearts.
Doctoral thesis , UCL (University College London).
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Abstract
Background- Coronary heart disease is the leading cause of death in the Western world and targeting those strategies which limit the damage sustained as a result of a lethal myocardial infarction has been a major goal for many years. Two such strategies, ischaemic preconditioning and ischaemic postconditioning are the most powerful endogenous cardio-protective phenomena known to man. The mechanisms involved in the newly described phenomenon of ischaemic postconditioning are not fully known. Additionally, the vast majority of studies investigating ischaemic preconditioning have been performed in normal hearts, leading to the suggestion that preconditioning is a "healthy heart" phenomenon. However, conflicting evidence exists as to whether the diabetic myocardium can be protected by ischaemic preconditioning (IPC). This thesis examines the mechanisms involved in these strategies of cardioprotection: (1) ischaemic postconditioning in normal hearts, and (2) ischaemic pre- and postconditioning in type II diabetic hearts. Methods and Results- Using a Langendorff isolated rat heart model we demonstrated that ischaemic postconditioning significantly reduced myocardial infarct size in normal rat hearts, and that this effect was comparable to that of ischaemic preconditioning. Western blot analysis demonstrated for the first time that postconditioning-induced protection is mediated via the PI3K-Akt pro- survival signalling cascade and its downstream targets, namely, eNOS and p70S6K. However, we found that type II diabetic rat hearts could not be protected using the same postconditioning protocol as a result of insufficient Akt phosphorylation. Conversely, the type II diabetic myocardium can be protected by ischaemic preconditioning but the threshold required to achieve this protection is elevated compared to non-diabetic hearts. This elevation in threshold is required to achieve sufficient phosphorylation of Akt, to execute the protective signal induced by ischaemic preconditioning. Conclusion- Our study demonstrates that in normal hearts, ischaemic postconditioning is a powerful strategy for myocardial protection and is mediated via the PI3K-Akt pro-survival signalling cascade. However, presumably due to differences in cellular signalling physiology, ischaemic postconditioning does not have a similar effect in type II diabetic hearts, and the beneficial effect of ischaemic preconditioning is only seen if the preconditioning stimulus is increased sufficiently to achieve enough Akt phosphorylation to mediate the protective signal. This suggests that the human diabetic population may be more resistant to the protective effects of IPC, but that provided the preconditioning stimulus is sufficient, the diabetic myocardium can be protected.
| Type: | Thesis (Doctoral) |
|---|---|
| Title: | Ischaemic postconditioning in normal and type 2 diabetic rat hearts |
| Identifier: | PQ ETD:593542 |
| Open access status: | An open access version is available from UCL Discovery |
| Language: | English |
| Additional information: | Thesis digitised by ProQuest. |
| URI: | https://discovery-pp.ucl.ac.uk/id/eprint/1446210 |
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