Dana, Ali; (2001) Adenosine A1 receptor induced delayed preconditioning: Investigation of the time course and cellular mechanisms. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

Introduction: Ischaemic heart disease is the leading cause of mortality and morbidity in the Western world. The possibility of exploiting an innate adaptive mechanism to protect ischaemic myocardium has generated considerable excitement and enthusiastic research. Brief periods of ischaemia induce subacute myocardial protection against subsequent ischaemic injury, a phenomenon termed delayed preconditioning which appears to be mediated by adenosine. The temporal profile and the cellular mechanisms underlying this delayed adaptation in experimental animals and in patients with coronary artery disease were the subject of this thesis. Methods and Results: In experimental studies, delayed preconditioning was induced in in vivo rabbit and in vitro rat models of regional myocardial ischaemia-reperfusion with the selective adenosine A1 receptor (A1R) agonist 2-chloro-N6-cyclopentyladenosine (CCPA). Infarct size expressed as a percentage of risk zone was nearly halved by prior intermittent A1R activation with CCPA (5 doses at 48h intervals) implying that animals had been maintained in a preconditioned state over 10 days. Using selective inhibitors, it was demonstrated that A1R induced delayed preconditioning is dependent on a signalling mechanism involving protein kinase C (PKC) and tyrosine kinases (TKs). Downstream of these kinases, A1R activation induced subacute activation of p38 MAPK, phosphorylation of Hsp27 and enhanced expression of Mn-SOD, implying involvement of these cytoprotective proteins in mediating delayed protection. No role was demonstrated for a nitric oxide-dependent pathway in induction of protection. Delayed myocardial protection, in terms of enhanced tolerance to ischaemia during exercise was demonstrated in patients with coronary artery disease. This adaptation was independent of adenosine. Conclusions: These results suggest that the cellular events downstream of A1R involve both PKC and TKs which in turn, results in phosphorylation/activation of Hsp27, and enhanced activity of Mn-SOD, two potential end-effectors of delayed cardioprotection. The exercise study is the first to demonstrate delayed preconditioning in man. The ability to maintain myocardium in a protected state over several days suggests that A1R activation may hold promise as a new approach to long-term cardioprotection in patients at increased risk of myocardial infarction.

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