Bromage, DI; (2016) The potential role of stromal derived factor 1α in remote ischaemic conditioning. Doctoral thesis , UCL (University College London).

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Abstract

Background Alleviating the injury associated with ST-elevation myocardial infarction is central to improving the global burden of coronary heart disease. The chemokine stromal cell-derived factor 1α (SDF-1α) and its receptor, CXCR4, have dual potential benefit in this regard: acutely protecting the heart from lethal ischaemia-reperfusion injury (IRI) whilst mitigating adverse ventricular remodelling by recruiting progenitor cells to the site of injury. This project hypothesised that SDF-1α mediates the acute cardioprotection conferred by remote ischaemic conditioning (RIC), the phenomenon whereby brief cycles of non-lethal tissue ischaemia and reperfusion remote from the heart protects against myocardial IRI. Methods and Results This thesis defines a paradigm for evidencing a role in RIC that includes induction of cardioprotection by exogenous administration of SDF-1α at the time of reperfusion, abolition of cardioprotection by specific antagonism of CXCR4, increased production of SDF-1α as a direct effect of RIC, and absence of cardioprotection in CXCR4-deficient mice. A murine in vivo model of myocardial IRI and a novel ELISA for active SDF-1α were established and used to investigate this paradigm. This thesis provides the first description of cardioprotection against myocardial IRI as a result of exogenous SDF-1α administered prior to reperfusion. Moreover, AMD3100, a highly specific inhibitor of CXCR4, abolishes the beneficial effect of RIC in vivo. Next, SDF-1α cleavage and inactivation was unexpectedly demonstrated to increase after RIC, which may be attributable to up-regulation of dipeptidyl peptidase-4. Finally, inducible cardiomyocyte-specific CXCR4 deletion unexpectedly conferred protection against myocardial IRI. The protective mechanism was not established and, furthermore, it prohibited the use of these mice in experiments to validate the role of CXCR4 signalling in RIC. Conclusions The intrinsic role of SDF-1α in RIC remains equivocal. However, modulation of the SDF-1α-CXCR4 axis with other approaches, including exogenous SDF-1α, has potential utility in cardioprotection against myocardial IRI.

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