The symposium focused on signalling of injury and protection in the clinical frame of acute myocardial ischemia. Especially protection afforded by brief episodes of ischemia and reperfusion before infarction (preconditioning), and protection afforded by ischemia and reperfusion at the start of reperfusion (postconditioning), was discussed.
The first speaker, Marcus Schaub from
Zurich , Switzerland , had used microarray gene analysis after ischemic preconditioning, pharmacological preconditioning with volatile anaesthetics, and compared the genomics with that after ischemia and after postconditioning. His main finding were that the clusters of genes which were upregulated were very different depending on the mode of protection. There was some discussion of the relevance of doing genomics when the results of gene regulation are beyond the time frame of the biological events taking place, but that was well addressed by Schaub who pointed out that genomics were important for identification of future therapies, and that he had clinical data not presented here which supported this.
Derek Hausenloy from London , UK , talked about the reperfusion injury salvage (RISK) pathway, which involves cascades of phosphorylated protein kinases such as PI3K, Akt, ERK1/2, and GSK3b. According to Hausenloy the RISK pathway is involed in the protectiove signalling underlying ischemic as well as pharmacological preconditioning, in addition to postconditioning. The end effectors of RISK may be reduced apoptosis, decreased Ca loading, reduced gap junction conductance, reduced opening of the mitochondrial permeability transition pore (mPTP), and reduced ROS-formation. A concern from the audience was that all evidence for the RISK involvement is forwarded by the use of “dirty drugs”.
Kerstin Boengler, Essen , Germany , spoke about connexion 43 in myocardial protection. Connexin 43 is located in the inner mitochondrial membrane in hearts from humans, pigs, rabbits, rats, and mice, to where it is recruited and transported by heat shock protein 90. Mice with gene deletion of connexion 43 can not be proteced by preconditioning. In the prescence of the ROS-donor menadion, however, this finding is reversed. Connexin 43 deficient mice can be protected by postconditioning. In the aged heart connexion 43 expression is reduced, comcomitant with reduced effect of preconditioning.
Michel Ovize, Lyon , France , had the last talk on the role of the mPTP. Opening of the mPTP during postischemic reperfusion leads to cell death by apoptosis and necrosis. ROS (in large amounts, as opposed to the small amounts evoking myocardial protection) contribute to opening of the pore. Cyclosporine A, which desensitizes the mPTP, reduces myocardial infarction, while cyclofilin D deficient mice, which have reduced mPTP opening, also had reduced infarcts.