Ischemic but not pharmacological preconditioning elicits a gene expression profile similar to unprotected myocardium

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Abstract
Pharmacological (PPC) and ischemic preconditioning (IschPC) provide comparable protection against ischemia in the heart. However, the genomic phenotype may depend on the type of preconditioning. Isolated perfused rat hearts were used to evaluate transcriptional responses to PPC and IschPC in the presence (mediator/effector response) or absence (trigger response) of 40 min of test ischemia using oligonucleotide microarrays. IschPC was induced by 3 cycles of 5 min of ischemia, and PPC by 15 min of 2.1 vol% isoflurane. Unsupervised analysis methods were used to identify gene expression patterns. PPC and IschPC were accompanied by marked alterations in gene expression. PPC and IschPC shared only ∼25% of significantly up- and downregulated genes after triggering. The two types of preconditioning induced a more uniform genomic response after ischemia/reperfusion. Numerous genes separated preconditioned from unprotected ischemic hearts. Three stable gene clusters were identified in the trigger response to preconditioning, while eight stable clusters related to cytoprotection, inflammation, remodeling, and long interspersed nucleotide elements (LINEs) were delineated after prolonged ischemia. A single stable sample cluster emerged from cluster analysis for both IschPC and unprotected myocardium, indicating a close molecular relationship between these two treatments. Principal component analysis revealed differences between PPC vs. IschPC, and trigger vs. mediator/effector responses in transcripts predominantly related to biosynthesis and apoptosis. IschPC and PPC similarly but distinctly reprogram the genetic response to ischemic injury. IschPC elicits a postischemic gene expression profile closer to unprotected myocardium than PPC, which may be therefore more advantageous as therapeutic strategy in cardioprotection.