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Novel Signalling Pathways in Myocardial Conditioning Against Reperfusion Injury

Sharma, V; (2013) Novel Signalling Pathways in Myocardial Conditioning Against Reperfusion Injury. Doctoral thesis (PhD), UCL (University College London). Green open access

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Abstract

Ischaemic preconditioning (IPC) and insulin protect the heart against lethal ischaemia-reperfusion (IR) by activating cardioprotective kinases such as PI3K-AKT. This thesis explores the effect of endothelial dysfunction, as seen in diabetes - a major risk factor for ischaemic heart disease, on IPC using the ESMIRO mice. These mice have dysfunctional vascular insulin receptors as well as endothelial dysfunction similar to that present in diabetes. Further, the effect of vascular insulin resistance on the ability of insulin to condition the heart against IR injury is investigated. The thesis also investigates the post-translational modification of a proapoptotic protein, BNIP3, as a possible mechanism of IPC. BNIP3 appears to a play a central role in mediating cell death in response to IR. The Langendorff technique of perfusing isolated mouse hearts was used. No change was noted in the total amount of BNIP3 in C57BL/6J mouse hearts in response to IR or IPC, though IR increased the measured amount of the carboxy-terminal end of BNIP3, a crucial effector of BNIP3 mediated cell death. IPC prevents this increase in the carboxy terminal end of BNIP3. BNIP3 phosphorylation occured in response to both IPC and IR. Thus, IPC may lead to a post-translational modification in BNIP3 preventing IR mediated increase in the carboxy-terminal of BNIP3. This is independent of BNIP3 phosphorylation. The IPC protocols used failed to significantly protect the ESMIRO mice and their wildtype littermates (WT) against IR injury or activate AKT. Furthermore insulin treatment did not significantly protect the ESMIRO mice and the WT against IR injury though, unexpectedly, AKT activation was seen in both with insulin. Finally, ESMIRO mice are more resistant than their WT littermates to an increase in ischaemic period before reperfusion. Hence, insulin transport across the endothelium appears to be independent of the insulin receptors. Ischemic tolerance noted in ESMIRO mice has also been reported in diabetes, implying that a possible mechanism underlying this ischemic tolerance may be vascular dysfunction which is common to both the ESMIRO mice and the diabetic phenotype.

Type: Thesis (Doctoral)
Qualification: PhD
Title: Novel Signalling Pathways in Myocardial Conditioning Against Reperfusion Injury
Open access status: An open access version is available from UCL Discovery
Language: English
UCL classification: UCL > Provost and Vice Provost Offices
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Pop Health Sciences > Institute of Cardiovascular Science
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Pop Health Sciences > Institute of Cardiovascular Science > Hatter Cardiovascular Institute
URI: https://discovery.ucl.ac.uk/id/eprint/1407936
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